Compounds and compositions for the inhibition of NAMPT

ABSTRACT

The present invention relates to compounds and composition for inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below.

CLAIM OF PRIORITY

This application claims priority from PCT International Application No.PCT/US2011/050301, filed on Sep. 2, 2011, which claims priority fromU.S. provisional application Ser. No. 61/482,537, filed on May 4, 2011,the content of each of which is fully incorporated herein by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds and composition forinhibition of Nicotinamide phosphoribosyltransferase (“NAMPT”), theirsynthesis, applications and antidote.

BACKGROUND OF THE INVENTION

Nicotinamide adenine dinucleotide (NAD) plays fundamental roles in bothcellular energy metabolism and cellular signaling. In energy metabolism,the chemistry of the pyridine ring allows NAD to readily accept anddonate electrons in hydride transfer reactions catalyzed by numerousdehydrogenases.

The preparation of a class of compounds, comprising several subclasses,which act as inhibitors of the formation of nicotinamide adenylnucleotide, and their use thereof as anti-tumour agents, is alreadydescribed in the patent applications WO00/50399, WO97/48695, WO97/48696,WO97/48397, WO99/31063, WO99/31060, WO99/31087, WO99/31064, WO00/50399,and WO03/80054.

One of these inhibitors,(E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridine-3-yl)-a crylamidealso known as APO866, FK866, WK175, or WK22.175 and hereinafter referredto as FK866 [International Non-proprietary Name], is especiallydescribed in the literature as an anticancer agent. FK866 may be usedfor treatment of diseases implicating deregulated apoptosis such ascancer. It has been demonstrated in the prior art that FK866 interfereswith nicotinamide adenyl dinucleotide (also known and hereinafterreferred to as NAD) biosynthesis and induces apoptotic cell deathwithout any DNA damaging effects.

Additionally, FK866((E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)acrylamide)induces apoptosis in HepG2 cells without having primary effects oncellular energy metabolism. (Hasmann M, Schemainda I. FK866, a HighlySpecific Noncompetitive Inhibitor of NicotinamidePhosphoribosyltransferase, Represents a Novel Mechanism for Induction ofTumor Cell Apoptosis. Cancer Res 2003; 63:7436-7442. [PubMed: 14612543])Instead of causing immediate cytotoxicity, it inhibits NAMPT anddepletes the cells of NAD, suggesting that FK866 could be a promisingagent against cancer cells that rely on nicotinamide to synthesize NAD.The crystal structure of the NAMPT-FK866 complex reveals that thecompound binds at the nicotinamide-binding site of NAMPT to inhibit itsactivity. FK866 has been tested in a murine renal cell carcinoma modeland shown to display anti-tumor, antimetastatic, and anti-angiogenicactivities (Drevs J, et al. Antiangiogenic potency of FK866/K22.175, anew inhibitor of intracellular NAD biosynthesis, in murine renal cellcarcinoma. Anticancer Res 2003; 23:4853-4858. [PubMed:14981935]).

In a mouse mammary carcinoma model, FK866 also induces a delay in tumorgrowth and an enhancement in tumor radiosensitivity accompanied withdose-dependent decreases in NAD levels, pH, and energy status. Achemosensitizing effect of FK866 has also been observed onanti-neoplastic 1-methyl-3-nitro-1-nitrosoguanidinium (MNNG)-inducedcell death in THP-1 and K562 leukemia cell lines (Pogrebniak A, et al.Chemopotentiating effects of a novel NAD biosynthesis inhibitor, FK866,in combination with antineoplastic agents. Eur J Med Res 2006;11:313-321. [PubMed: 17052966]).

The efficacy of GMX1777 was evaluated in xenograft models and thepharmacokinetic profile of GMX1778 and its effect on nicotinamideadenine dinucleotide cellular levels was measured by liquidchromatography/mass spectrometry. (Beauparlant P., et al. Preclinicaldevelopment of the nicotinamide phosphoribosyl transferase inhibitorprodrug GMX1777. Anticancer Drugs. 2009 Jun; 20(5):346-54).

GMX1777 is a water-soluble intravenously administered prodrug of GMX1778that Gemin X in-licensed from LEO Pharma (LEO numbers: EB1627 andCHS828, respectively). These compounds and other substitutedcyanoguanidines have the structures of Table 1. None of the compounds ofthe present invention are cyanoguanidines.

TABLE 1

A

C

B1

B2Substituted Cyanoguanidines with Defined Pharmacological Effects:

-   A Cytotoxic CHS 828;-   B Potassium channel openers pinacidil (B1) and 12 g of compound as    described in Perez-Medrano et al (B2); and-   C Histamine-II receptor antagonist cimetidine. (from Lövborg et al.    BMC Research Notes 2009 2:114 doi:10.1186/1756-0500-2-114).

More recently, CHS-828 has been identified as a NAMPT inhibitor (OlesenU H, et al. Anticancer agent CHS-828 inhibits cellular synthesis of NAD.Biochem Biophys Res Commun 2008; 367:799-804. [PubMed: 18201551]).CHS-828 has been shown that this compound potently inhibits cell growthin a broad range of tumor cell lines, although the detailed mechanismfor this inhibitory effect of CHS-828 remains undetermined (Ravaud A, etal. Phase I study and guanidine kinetics of CHS-828, aguanidine-containing compound, administered orally as a single doseevery 3 weeks in solid tumours: an ECSG/EORTC study. Eur J Cancer 2005;41:702-707. [PubMed: 15763645]). Both FK866 and CHS-828 are currently inclinical trials for cancer treatments.

There are numerous uses for drugs which inhibit NAMPT.

Lack of NAMPT expression strongly affects development of both T and Blymphocytes. By using mutant forms of this protein and awell-characterized pharmacological inhibitor (FK866), authorsdemonstrated that the ability of the NAMPT to regulate cell viabilityduring genotoxic stress requires its enzymatic activity. Collectively,these data demonstrate that NAMPT participates in cellular resistance togenotoxic/oxidative stress, and it may confer to cells of the immunesystem the ability to survive during stressful situations such asinflammation. (Rongvaux, A., et al. The Journal of Immunology, 2008,181: 4685-4695).

NAMPT may also have effects on endothelium (EC) in relation to highglucose levels, oxidative stress and on aging. It is also believed thatNAMPT may enable proliferating human EC to resist the oxidative stressof aging and of high glucose, and to productively use excess glucose tosupport replicative longevity and angiogenic activity.

SUMMARY OF THE INVENTION

One aspect of this invention is the provision of compounds,compositions, kits, and antidotes for the NAMPT pathway in mammalshaving a compound of the Formula I:

wherein

-   R is aryl or heteroaryl, wherein the heteroatom of said heteroaryl    numbers 1, 2 or 3, and is independently selected from N, S or O,    further wherein each of said aryl and heteroaryl may independently    be either substituted or fused with an aryl or heteroaryl, still    further wherein any of said aryl and heteroaryl is either    unsubstituted or optionally independently substituted with one or    more substituents which can be the same or different and are    independently selected from the group consisting of:    -   deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-,        —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),        —C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl,        -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-,        —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl, -cycloalkyl,        -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that        no two adjacent ring heteroatoms are both S or both O;-   Ar is aryl or heteroaryl, each of said aryl and heteroaryl being    either unsubstituted or optionally independently substituted with 1,    2, 3 or 4 substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),    —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy,    (alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl;-   R¹ is cycloalkyl, —CH_(z)F_(3-z), aryl, heterocycloalkyl,    heteroaryl, alkyl, -alkenyl, -alkynyl, (aryl)alkyl-,    (heteroaryl)alkyl- or (heterocycloalkyl)alkyl-, (i) wherein each of    said cycloalkyl, aryl, heterocycloalkyl, heteroaryl and alkyl is    either unsubstituted or optionally substituted with 1, 2, 3, 4 or 5    substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),    —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-,    (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl,    (heterocycloalkyl)alkyl-, -aryl, (aryl)alkyl-, -heteroaryl,    (heteroaryl)alkyl-, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂—CF₃,    —C(O)N(alkyl)₂, —C(O)alkyl, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl,    —S(O₂)NH₂, —S(O₂)NH(alkyl), —S(O₂)N(alkyl)₂, —N(H)S(O₂)(alkyl),    —C(O)N(H)(alkyl), and methylenedioxy, (ii) further wherein each of    said cycloalkyl, aryl, heterocycloalkyl, and heteroaryl may    optionally additionally optionally be fused with independently    selected aryl, heteroaryl, heterocycloalkyl or cycloalkyl;-   R³ is H, alkyl or arylalkyl-;-   X is S, S(O), S(O)₂, S(O)₂NH, O or C(O);-   n is 0, 1, 2, 3 or 4;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1 or 2; and-   z is 0, 1 or 2;    and pharmaceutically acceptable salts, solvates, esters, prodrugs    and isomers thereof.

Another embodiment of the invention is compounds of Formula I, whereX═SO₂, n=1, m=0 and t=0, whereby the formula becomes Formula IA

Another aspect of the invention is compounds of Formula IA where R ispyridine and the Formula becomes Formula IB:

wherein:

-   Ar is aryl or heteroaryl, each of said aryl and heteroaryl being    either unsubstituted or optionally independently substituted with 1,    2, 3 or 4 substituents which can be the same or different and are    independently selected from the group consisting of:    -   deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-,        —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),        —C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl,        -alkenyl, -alkynyl, -alkoxy, (alkoxyalkyl)amino-,        —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl;-   R¹ is —NR^(a)R^(b), wherein R^(a) is H, alkyl or —S(O)₂alkyl and    R^(b) is alkyl, hydroxyalkyl, —S(O)₂alkyl, —(CH₂)_(q)cycloalkyl,    —(CH₂)_(q)heterocycloalkyl, aryl, arylalkyl-, —(CH₂)_(q)heteroaryl;    -   cycloalkyl;    -   heterocycloalkyl;    -   aryl;    -   heteroaryl;        -   each of said cycloalkyl, heterocycloalkyl, aryl, or            heteroaryl is unsubstituted or substituted with 1, 2, 3, 4            or 5 substituents which can be the same or different and are            independently selected from the group consisting of:            -   deuterium, halo, cyano, alkyl, hydroxyl, hydroxyalkyl,                hydroxyalkoxy, cyanoalkyl, haloalkyl, alkenyl, alkynyl,                alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy,                benzyloxy, oxo, —(CH₂)_(q)—NR^(c)R^(d),                —(CH₂)_(q)—CONR^(c)R^(d), —S(O)₂-alkyl, —S(O)₂-aryl,                S(O)₂NH₂, —S(O)₂NH-alkyl, —S(O)₂N(alkyl)₂,                —S(O)₂-heterocycloalkyl, —S(O)₂—CF₃, —C(O)alkyl,                —C(O)aryl, —C(O)alkylenylaryl, —C(O)O-alkyl,                —NH—C(O)alkyl, —NH—C(O)aryl, methylenedioxy,                —(CH₂)_(q)cycloalkyl, cycloalkylalkoxy-, aryl,                arylalkyl-, —(CH₂)_(q)heteroaryl, and                —(CH₂)_(q)heterocycloalkyl,            -   wherein each of said cycloalkyl, heterocycloalkyl, aryl                or heteroaryl may be substituted by one or more halo,                nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl,                haloalkyl, or alkoxy and;-   R^(c) and R^(d) are independently selected from the group consisting    of H, alkyl, hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, —S(O)₂alkyl    and cycloalkyl or R^(c) and R^(d) can form a 5 or 6 membered    heterocycloalkyl group together with the nitrogen atom to which they    are attached, wherein said heterocycloalkyl group may contain one or    more additional heteroatom(s) selected from N, S or O;-   z is 0, 1 or 2;-   q is 0, 1, 2, 3 or 4;    and pharmaceutically acceptable salts thereof, with the proviso that    the compound of formula IB is not:-   N-[3-(cyclopentylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[2-(1-methylethoxy)-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[2-ethoxy-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[5-[(hexahydro-1Hazepin-1-yl)sulfonyl]-2-(2,2,2-trifluoroethoxy)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[5-[(diethylamino)sulfonyl]-2-(4-morpholinyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[3-[[(3-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[3-[[(4-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;-   3-(3-pyridinyl)-N-[4-[[(tetrahydro-1,1-dioxido-3-thienyl)amino]sulfonyl]phenyl]-2-propenamide;-   3-(3-pyridinyl)-N-[3-[[[3-(trifluoromethyl)phenyl]amino]sulfonyl]phenyl]-2-propenamide;    and-   3-(3-pyridinyl)-N-[1,4,5,6-tetrahydro-5-[(4-methylphenyl)sulfonyl]pyrrolo[3,4-c]pyrazol-3-yl]-2-propenamide.

Another embodiment of the invention is compounds of Formula IB where Aris phenyl and the Formula becomes Formula IC:

wherein:

-   R¹ is —NR^(a)R^(b), wherein R^(a) is H, R^(b) is unsubstituted or    substituted aryl;    -   cycloalkyl;    -   aryl;    -   heterocycloalkyl;    -   heteroaryl;        -   each of said cycloalkyl, heterocycloalkyl, aryl, or            heteroaryl is unsubstituted or substituted with 1, 2, 3, 4            or 5 substituents which can be the same or different and are            independently selected from the group consisting of:            -   halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy,                —C(O)NR^(c)R^(d), heteroaryl, heterocycloalkyl, aryl,                —NHS(O)₂alkyl, —S(O)₂alkyl and —S(O)₂NH₂;-   R^(c) and R^(d) are independently selected from H, alkyl and    cycloalkyl; and pharmaceutically acceptable salts thereof.

Another aspect of this invention is the provision of methods of treatinga disease via the inhibition of NAMPT in a subject (e.g., a human) inneed thereof by administering to the subject an effective amount of thecompound or the pharmaceutical formulation of the present invention.

Still another aspect of this invention is to provide a method fortreating, preventing, inhibiting or eliminatin a sisease or condition ina patient by inhibiting NAMPT in said patient by administering atherapeutically effective amount of at least one compound of thedisclosure, wherein said disesase or donditon is selected from the groupconsisting of cancer, ovarian ancer, breat cancer, uterine cancer, coloncancer, cervical cancer, lung cancer, protate cancer, skin cancer,bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodkins' disease,viral infection, Human Immunodeficiencey Virus, hepatitis virus, hermpesfirus, herpes simplex, inflammatory disorders, irritable bowel syndrome,inflammatory bowel disease, rheumatoid arthritis, asthma, chronicobsturcive pulmonary disease, osteroarthritis, osteoporosis, dermatitis,atotic dermatitits, psoriasis, systemic lupus erythematois, multiplesclerosis, psoriatic arthritis, ankylosing spndylitis, fraft ersus hostdisease, Alzheimer disease, cardiovascular accident, atherosclerosois,diabetes, glomeruloneprhitis, metabolic syndrome, non-small cell unlgcancer, small cell lung cancer, multiple mueloma, leukemia, lympomas,squamous cell cancers, kidney cancer, uteral and bladder cancers, cancerof head and neck, cancers of the brain and central nervous system.

Another preferred embodiment is a pharmaceutical formulation comprisinga pharmaceutically acceptable compound of the present invention, whichprovides, upon administration to a human, a decrease in tumor burdenand/or metastases. The pharmaceutical formulation can be administered byoral means or other suitable means.

Yet another embodiment is a method of treating ovarian cancer in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating colon cancer in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating breast cancer in asubject (e.g., a human) in need thereof by administering to the subjectan effective amount of the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating leukemia in a subject(e.g., a human) in need thereof by administering to the subject aneffective amount of the compound or the pharmaceutical formulation ofthe present invention.

Yet another embodiment is a method of treating colon cancer, before orafter surgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention.

Yet another embodiment is a method of treating cancer, before or aftersurgical resection and/or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy to treat nausea, with or withoutdexamethasone.

Yet another embodiment is a method of treating cancer, before or aftersurgical resection and or radiation therapy, in a subject (e.g., ahuman) in need thereof by administering to the subject an effectiveamount of the compound or the pharmaceutical formulation of the presentinvention, including adjunctive therapy with one or more additionaltherapeutic agents, or their pharmaceutically acceptable salts thereof.Non-limiting examples of such additional therapeutic agents includecytotoxic agents (such as for example, but not limited to, DNAinteractive agents (such as cisplatin or doxorubicin)); taxanes (e.g.taxotere, taxol); topoisomerase II inhibitors (such as etoposide);topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar,or topotecan); tubulin interacting agents (such as paclitaxel, docetaxelor the epothilones); hormonal agents (such as tamoxifen); thymidilatesynthase inhibitors (such as 5-fluorouracil or 5-FU); anti-metabolites(such as methoxtrexate); alkylating agents (such as temozolomide,cyclophosphamide); Farnesyl protein transferase inhibitors (such as,SARASAR™.(4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,-6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoehtyl]-1-piperidine-carboxamide,or SCH 66336), tipifarnib (Zarnestra® or R115777 from JanssenPharmaceuticals), L778,123 (a farnesyl protein transferase inhibitorfrom Merck & Company, Whitehouse Station, N.J.), BMS 214662 (a farnesylprotein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals,Princeton, N.J.); signal transduction inhibitors (such as, Iressa® (fromAstra Zeneca Pharmaceuticals, England), Tarceva® (EGFR kinaseinhibitors), antibodies to EGFR (e.g., C225), GLEEVEC® (C-abl kinaseinhibitor from Novartis Pharmaceuticals, East Hanover, N.J.);interferons such as, for example, Intron® (from Merck & Company),Peg-Intron® (from Merck & Company); hormonal therapy combinations;aromatase combinations; ara-C, adriamycin, cytoxan, and gemcitabine.

Other anti-cancer (also known as anti-neoplastic) agents include but arenot limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin (ELOXATIN®. from Sanofi-Synthelabo Pharmaceuticals, France),Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade®, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Ifosfomide, Rituximab, C225, and Campath, 5-fluorouracil and leucovorin,with or without a 5-HT₃ receptor inhibitor (e.g., dolansetron,granisetron, ondansetron) with or without dexamethasone.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein, oras known to those skilled in the art, and the other pharmaceuticallyactive agent or treatment within its dosage range. For example, the CDC2inhibitor olomucine has been found to act synergistically with knowncytotoxic agents in inducing apoptosis (J. Cell Sci., (1995) 108, 2897).The compounds of the invention may also be administered sequentiallywith known anticancer or cytotoxic agents when a combination formulationis inappropriate. In any combination treatment, the invention is notlimited in the sequence of administration; compounds of the inventionmay be administered either prior to or after administration of the knownanticancer or cytotoxic agent. For example, the cytotoxic activity ofthe cyclin-dependent kinase inhibitor flavopiridol is affected by thesequence of administration with anticancer agents. Cancer Research,(1997) 57, 3375. Such techniques are within the skills of personsskilled in the art as well as attending physicians.

Any of the aforementioned methods may be augmented by administration offluids (such as water), loop diuretics, one or more of achemotherapeutic or antineoplastic agent, such as leucovorin andfluorouracil, and an adjunctive chemotherapeutic agent (such asfilgrastim and erythropoietin), or any combination of the foregoing.

Yet another embodiment is a method for administering a compound of theinstant invention to a subject (e.g., a human) in need thereof byadministering to the subject the pharmaceutical formulation of thepresent invention.

Yet another embodiment is a method of preparing a pharmaceuticalformulation of the present invention by mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable additives orexcipients.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally or intravenously.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, preferably fromabout 1 mg to about 500 mg, more preferably from about 1 mg to about 250mg, still more preferably from about 1 mg to about 25 mg, according tothe particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two tofour divided doses.

DEFINITIONS

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings. If a definition is missing, convention definition as known toone skilled in the art controls.

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

The term “inhibitor” refers to a molecule such as a compound, a drug, anenzyme activator or a hormone that blocks or otherwise interferes with aparticular biologic activity.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system. For example, an “effective amount” for therapeuticuse is the amount of the composition comprising a compound as disclosedherein required to provide a clinically significant decrease in adisease. An appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation. Thus, the expression “effective amount” generallyrefers to the quantity for which the active substance has therapeuticeffects. In the present case the active substance is the inhibitor ofthe formation of Nicotinamide phosphoribosyltransferase (NAMPT).

As used herein, the terms “treat” or “treatment” are synonymous with theterm “prevent” and are meant to indicate a postponement of developmentof diseases, preventing the development of diseases, and/or reducingseverity of such symptoms that will or are expected to develop. Thus,these terms include ameliorating existing disease symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disorder or disease, e.g., arrestingthe development of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

By “pharmaceutically acceptable” or “pharmacologically acceptable” ismeant a material which is not biologically or otherwise substantiallyundesirable, i.e., the material may be administered to an individualwithout causing any substantially undesirable biological effects orinteracting in a deleterious manner with any of the components of thecomposition in which it is contained.

“Carrier materials” or what are also referred to as “excipients” includeany commonly used excipients in pharmaceutics and should be selected onthe basis of compatibility and the release profile properties of thedesired dosage form. Exemplary carrier materials include, e.g., binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” may comprise,e.g., acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, sodium caseinate, soy lecithin, sodium chloride, tricalciumphosphate, dipotassium phosphate, sodium stearoyl lactylate,carrageenan, monoglyceride, diglyceride, pregelatinized starch, and thelike. See, e.g., Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975.

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

As used herein, “alkyl” means a straight chain or branched saturatedchain having from 1 to 10 or 1 to 6 carbon atoms. Representativesaturated alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl and the like, and longer alkyl groups, such asheptyl, and octyl and the like. An alkyl group can be unsubstituted orsubstituted. Alkyl groups containing three or more carbon atoms may bestraight, branched or cyclized. As used herein, “lower alkyl” means analkyl having from 1 to 6 carbon atoms.

As used herein, an “alkenyl group” includes an unbranched or branchedhydrocarbon chain having one or more double bonds therein. The doublebond of an alkenyl group can be unconjugated or conjugated to anotherunsaturated group. Illustrative alkenyl groups include, but are notlimited to, (C₂-C₈) or (C₂-C₆) alkenyl groups, such as ethylenyl, vinyl,allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl,2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl andthe like. An alkenyl group can be unsubstituted or substituted.

The term “hydroxyalkyl” denotes an alkyl group as defined above whereinat least one of the hydrogen atoms of the alkyl group is replaced by ahydroxy group. Examples of hydroxyalkyl include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl,pentyl or n-hexyl wherein one or more hydrogen atoms are replaced by OH,as well as those hydroxyalkyl groups specifically illustrated by theexamples herein below.

The term “cyanoalkyl” denotes an alkyl group as defined above wherein atleast one of the hydrogen atoms of the alkyl group is replaced by acyano (—CN) group.

As used herein, “alkynyl group” includes an unbranched or branchedhydrocarbon chain having one or more triple bonds therein. The triplebond of an alkynyl group can be unconjugated or conjugated to anotherunsaturated group. Suitable alkynyl groups include, but are not limitedto, (C₂-C₆) alkynyl groups, such as ethynyl, propynyl, butyryl,pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,4-propyl-2-pentynyl, 4-butyl-2-hexynyl and the like. An alkynyl groupcan be unsubstituted or substituted.

The term “haloalkyl” denotes an alkyl group as defined above wherein atleast one of the hydrogen atoms of the alkyl group is replaced by ahalogen atom, preferably fluoro or chloro, most preferably fluoro.Examples of haloalkyl include, but are not limited to, methyl, ethyl,propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexylwherein one or more hydrogen atoms are replaced by Cl, F, Br or Iatom(s), as well as those haloalkyl groups specifically illustrated bythe examples herein below. Among the preferred haloalkyl groups aremonofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, forexample 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,fluoromethyl, trifluoromethyl.

The terms “trifluoromethyl,” “sulfonyl,” and “carboxyl” include CF₃,SO₂, and CO₂H, respectively.

The term “oxo” means ═O-group.

The term alkyl hydroxy or hydroxyalkyl means an alkyl group as definedabove, where the alkyl group has an OH group disposed thereon.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

The term “haloalkoxy” as used herein refers to an alkoxy group asdefined herein, wherein at least one of the hydrogen atoms of the alkoxygroup is replaced by a halogen atom, preferably fluoro or chloro, mostpreferably fluoro. Examples of haloalkoxy include trifluoromethoxy,trifluoroethoxy, difluoromethoxy and trifluoroethoxy.

The term “aminoalkyl” as used herein means a group having one or morenitrogen atoms and one or more alkyl groups as defined above on thenitrogen.

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Heteroarylalkyl” means a heteroaryl moiety as defined herein linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” means a heterocyclyl moiety as defined herein linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or in the invention, its definition on eachoccurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “deuterium” as used herein means a stable isotope of hydrogenhaving odd numbers of protons and neutrons.

The term “halo” as used herein means a substituent having at least onehalogen selected from fluorine, chlorine, bromine, and iodine.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom.

The term “(amino)alkoxy” as used herein means a substituent having atleast one amino group and at least one alkoxy group.

The term “aryloxy” as used herein means a substituent of the form Ar—O—where Ar is an aryl group as defined herein.

The term “methylenedioxy” as used herein means a functional group withthe structural formula —O—CH₂—O— which is connected to the molecule bytwo chemical bonds via the oxygens.

As used herein, “alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

The term “(alkoxyalkyl)amino” as used herein means a substituent havingat least one alkoxyalkyl group as defined above and at least one aminogroup as defined above.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein. Illustrative examples of aryl groupsinclude, but are not limited to phenyl, naphthalene and the followingmoieties:

and the like.

Illustrative substituted aryls include:

and the like.

As used herein, the term “heteroaryl” refers to a monocyclic, or fusedpolycyclic, aromatic heterocycle (ring structure having ring atomsselected from carbon atoms as well as nitrogen, oxygen, and/or sulfuratoms) having from 3 to 24 ring atoms per ring. The term “heteroaryl” asused herein also includes a monovalent aromatic radical of a 5-, 6-, or7-membered ring and includes fused ring systems (at least one of whichis aromatic) of 5-10 atoms containing at least one heteroatomindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups include, but are not limited to pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiromoieties are also included within the scope of this definition.Heteroaryl groups may be optionally substituted independently with oneor more substituents described herein. 5 or 6 membered heteroaryl can beselected from the group consisting of optionally substituted pyridinyl,pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl,pyridinone and benzimidazolyl. In a certain embodiment, heteroaryl isbicyclic heteroaryl selected from benzothiazole, dihydronaphthyridine,dihydropyridopyrimidine, dihydropyrrolopyridine, furopyridine,imidazopyrazine, imidazopyrazole imidazopyridine, imidazopyrimidine,indazole, indole, isoquinoline, naphthyridine, pyrazolopyridine,pyrrolopyridine, tetrazolopyridine, tetrahydroimidazopyridine,tetrahydropyrazolopyridine, thiazolopyridine and thienopyridine. In aanother embodiment, heteroaryl is bicyclic heteroaryl selected from1H-pyrazolo[3,4-b]pyridine; 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine;7,8-Dihydro-5H-pyrido[4,3-d]pyrimidine;5,7-Dihydro-pyrrolo[3,4-b]pyridine; 7,8-Dihydro-5H-[1,6]naphthyridine;1,4,6,7-Tetrahydro-imidazo[4,5-c]pyridine;1,8a-dihydroimidazo[1,2-a]pyridine; thieno[3,2-c]pyridine;1H-imidazo[1,2-b]pyrazole; 1H-pyrazolo[3,4-b]pyridine;furo[2,3-c]pyridine; 1H-pyrazolo[3,4-b]pyridine;1H-pyrrolo[3,2-c]pyridine; thieno[2,3-b]pyridine;imidazo[1,2-a]pyrimidine; furo[2,3-c]pyridine; isoquinoline;1H-indazole; imidazo[1,2-a]pyridine; thieno[2,3-c]pyridine;furo[2,3-c]pyridine; 1H-pyrrolo[2,3-c]pyridine; imidazo[1,2-a]pyrazine;1,3-benzothiazole; benzo[d]thiazole; 1H-pyrrolo[2,3-b]pyridine;[1,3]thiazolo[5,4-c]pyridine; [1,2,3,4]tetrazolo[1,5-a]pyridine;1,5-naphthyridine; 1H-indole; 1H-imidazo[4,5-c]pyridine; and1,6-naphthyridine.

By way of example and not limitation, carbon bonded heterocycles andheteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine,position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole ortetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine,position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5,6, 7, or 8 of an isoquinoline. Further examples of carbon bondedheterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl,6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl,3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles andheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Still moretypically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl,1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

The term “bicyclic heteroaryl” means a structure having atoms arrangedin two rings fused together with at least two atoms common to each ring,and at least one of the rings being a heteroaryl ring. Non limitingexamples of bicyclic heteroaryl comprise 5 to 14 membered bicyclicheteroaryl-groups comprising 1, 2, 3, or 4 heteroatoms independentlyselected from N, S or O. Illustrative examples of bicyclic heteroarylsinclude but are not limited to:

and the like.

Further examples of bicyclic heteroaryls include but are not limited to:

These bicyclic heteroaryl groups can be substituted as defined herein.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic or fused or spiro polycyclic, carbocycle havingfrom 3 to 24 or 3 to 6 ring atoms per ring. Illustrative examples ofcycloalkyl groups include, but are not limited to, the followingmoieties:

and the like.

As used herein, the term “heterocycloalkyl” refers to a monocyclic, orfused or spiro, polycyclic, ring structure that is saturated orpartially saturated and has from 3 to 24 ring atoms per ring selectedfrom C atoms and N, O, and S heteroatoms. Illustrative examples ofheterocycloalkyl and substituted heterocycloalkyl groups include, butare not limited to:

and the like.

Numerical ranges, as used herein, are intended to include sequentialwhole numbers. For example, a range expressed as “from 0 to 4” wouldinclude 0, 1, 2, 3 and 4.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

As used herein, the term “optionally substituted” means that thespecified group is unsubstituted or substituted by one or moresubstituents.

When a multifunctional moiety is shown, the point of attachment to thecore is indicated by a line. For e.g. (cycloalkyloxy)alkyl- refers toalkyl being the point of attachment to the core while cycloalkyl isattached to alkyl via the oxy group.

The expression “adjunctive chemotherapeutic agent” generally refers toagents which treat, alleviate, relieve, or ameliorate the side effectsof chemotherapeutic agents. Such agents include those which modify bloodcell growth and maturation. Examples of adjunctive chemotherapeuticagents include, but are not limited to, filgrastim and erythropoietin.Other such adjunctive chemotherapeutic agents include those whichinhibit nausea associated with administration of the chemotherapeuticagents, such as a 5-HT₃ receptor inhibitor (e.g., dolansetron,granisetron, or ondansetron), with or without dexamethasone.

The terms “chemotherapeutic agent” and “antineoplastic agent” generallyrefer to agents which treat, prevent, cure, heal, alleviate, relieve,alter, remedy, ameliorate, improve, or affect malignancies and theirmetastasis. Examples of such agents (also known as “antineoplasticagents”) include, but are not limited to, prednisone, fluorouracil(e.g., 5-fluorouracil (5-FU)), anastrozole, bicalutamide, carboplatin,cisplatin, chlorambucil, cisplatin, carboplatin, docetaxel, doxorubicin,flutamide, interferon-alpha, letrozole, leuprolide, megestrol,mitomycin, oxaliplatin, paclitaxel, plicamycin (Mithracin™), tamoxifen,thiotepa, topotecan, valrubicin, vinvlastin, vincristine, and anycombination of any of the foregoing. Additional such agents aredescribed later.

“Nicotinamide phosphoribosyltransferase” also named NAMPT, NMPRT,NMPRTase or NAmPRTase, (International nomenclature: E.C. 2.4.2.12) is akey enzyme in nicotinamide adenyl dinucleotide (NAD) biosynthesis fromthe natural precursor nicotinamide.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise.

When used as a therapeutic agent the inhibitors of the formation ofnicotinamide phosphoribosyltransferase (NAMPT) described herein may beadministered with one or more physiologically acceptable excipients. Aphysiologically acceptable carrier or excipient is a formulation towhich the compound can be added to dissolve it or otherwise facilitateits administration.

The dosage forms of the present invention, may contain a mixture of oneor more compounds of this invention, and may include additionalmaterials known to those skilled in the art as pharmaceuticalexcipients. Such pharmaceutical excipients include, for example, thefollowing: Stabilizing additives may be incorporated into the deliveryagent solution. With some drugs, the presence of such additives promotesthe stability and dispersibility of the agent in solution. Thestabilizing additives may be employed at a concentration ranging fromabout 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable, butnon-limiting, examples of stabilizing additives include gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine. The preferred stabilizing additives aregum acacia, gelatin and methyl cellulose.

Acidifying agents (acetic acid, glacial acetic acid, citric acid,fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid,nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,tartaric acid); Aerosol propellants (butane, dichlorodifluoro-methane,dichlorotetrafluoroethane, isobutane, propane,trichloromonofluoromethane); Air displacements (carbon dioxide,nitrogen); Alcohol denaturants (denatonium benzoate, methyl isobutylketone, sucrose octacetate); Alkalizing agents (strong ammonia solution,ammonium carbonate, diethanolamine, diisopropanolamine, potassiumhydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodiumhydroxide, trolamine); Anticaking agents (see glidant); Antifoamingagents (dimethicone, simethicone); Antimicrobial preservatives(benzalkonium chloride, benzalkonium chloride solution, benzelthoniumchloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridiniumchloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid,ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric nitrate, potassiumbenzoate, potassium sorbate, propylparaben, propylparaben sodium, sodiumbenzoate, sodium dehydroacetate, sodium propionate, sorbic acid,thimerosal, thymol); Antioxidants (ascorbic acid, acorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorousacid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol,tocopherols excipient); Buffering agents (acetic acid, ammoniumcarbonate, ammonium phosphate, boric acid, citric acid, lactic acid,phosphoric acid, potassium citrate, potassium metaphosphate, potassiumphosphate monobasic, sodium acetate, sodium citrate, sodium lactatesolution, dibasic sodium phosphate, monobasic sodium phosphate); Capsulelubricants (see tablet and capsule lubricant); Chelating agents (edetatedisodium, ethylenediaminetetraacetic acid and salts, edetic acid);Coating agents (sodium carboxymethylcellulose, cellulose acetate,cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceuticalglaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer,methylcellulose, polyethylene glycol, polyvinyl acetate phthalate,shellac, sucrose, titanium dioxide, carnauba wax, microcystalline wax,zein); Colorants (caramel, red, yellow, black or blends, ferric oxide);Complexing agents (ethylenediaminetetraacetic acid and salts (EDTA),edetic acid, gentisic acid ethanolmaide, oxyquinoline sulfate);Desiccants (calcium chloride, calcium sulfate, silicon dioxide);Emulsifying and/or solubilizing agents (acacia, cholesterol,diethanolamine (adjunct), glyceryl monostearate, lanolin alcohols,lecithin, mono- and di-glycerides, monoethanolamine (adjunct), oleicacid (adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene50 stearate, polyoxyl 35 caster oil, polyoxyl 40 hydrogenated castoroil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate80, propylene glycol diacetate, propylene glycol monostearate, sodiumlauryl sulfate, sodium stearate, sorbitan monolaurate, soritanmonooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid,trolamine, emulsifying wax); Filtering aids (powdered cellulose,purified siliceous earth); Flavors and perfumes (anethole, benzaldehyde,ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orangeflower oil, peppermint, peppermint oil, peppermint spirit, rose oil,stronger rose water, thymol, tolu balsam tincture, vanilla, vanillatincture, vanillin); Glidants and/or anticaking agents (calciumsilicate, magnesium silicate, colloidal silicon dioxide, talc);Humectants (glycerin, hexylene glycol, propylene glycol, sorbitol);Plasticizers (castor oil, diacetylated monoglycerides, diethylphthalate, glycerin, mono- and di-acetylated monoglycerides,polyethylene glycol, propylene glycol, triacetin, triethyl citrate);Polymers (e.g., cellulose acetate, alkyl celloloses,hydroxyalkylcelloloses, acrylic polymers and copolymers); Solvents(acetone, alcohol, diluted alcohol, amylene hydrate, benzyl benzoate,butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseedoil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, methylalcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanutoil, polyethylene glycol, propylene carbonate, propylene glycol, sesameoil, water for injection, sterile water for injection, sterile water forirrigation, purified water); Sorbents (powdered cellulose, charcoal,purified siliceous earth); Carbon dioxide sorbents (barium hydroxidelime, soda lime); Stiffening agents (hydrogenated castor oil,cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat,paraffin, polyethylene excipient, stearyl alcohol, emulsifying wax,white wax, yellow wax); Suspending and/or viscosity-increasing agents(acacia, agar, alginic acid, aluminum monostearate, bentonite, purifiedbentonite, magma bentonite, carbomer 934p, carboxymethylcellulosecalcium, carboxymethylcellulose sodium, carboxymethycellulose sodium 12,carrageenan, microcrystalline and carboxymethylcellulose sodiumcellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesiumaluminum silicate, methylcellulose, pectin, polyethylene oxide,polyvinyl alcohol, povidone, propylene glycol alginate, silicon dioxide,colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum);Sweetening agents (aspartame, dextrates, dextrose, excipient dextrose,fructose, mannitol, saccharin, calcium saccharin, sodium saccharin,sorbitol, solution sorbitol, sucrose, compressible sugar, confectioner'ssugar, syrup); Tablet binders (acacia, alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methycellulose, polyethylene oxide, povidone,pregelatinized starch, syrup); Tablet and/or capsule diluents (calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, microcrystalline cellulose, powdered cellulose,dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose,mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressiblesugar, confectioner's sugar); Tablet disintegrants (alginic acid,microcrystalline cellulose, croscarmellose sodium, corspovidone,polacrilin potassium, sodium starch glycolate, starch, pregelatinizedstarch); Tablet and/or capsule lubricants (calcium stearate, glycerylbehenate, magnesium stearate, light mineral oil, polyethylene glycol,sodium stearyl fumarate, stearic acid, purified stearic acid, talc,hydrogenated vegetable oil, zinc stearate); Tonicity agent (dextrose,glycerin, mannitol, potassium chloride, sodium chloride); Vehicle:flavored and/or sweetened (aromatic elixir, compound benzaldehydeelixir, iso-alcoholic elixir, peppermint water, sorbitol solution,syrup, tolu balsam syrup); Vehicle: oleaginous (almond oil, corn oil,cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate,mineral oil, light mineral oil, myristyl alcohol, octyldodecanol, oliveoil, peanut oil, persic oil, seame oil, soybean oil, squalane); Vehicle:solid carrier (sugar spheres); Vehicle: sterile (bacteriostatic waterfor injection, bacteriostatic sodium chloride injection);Viscosity-increasing (see suspending agent); Water repelling agent(cyclomethicone, dimethicone, simethicone); and Wetting and/orsolubilizing agent (benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docusate sodium, nonoxynol 9, nonoxynol 10,octoxynol 9, poloxamer, polyoxyl 35 castor oil, polyoxyl 40,hydrogenated castor oil, polyoxyl 50 stearate, polyoxyl 10 oleyl ether,polyoxyl 20, cetostearyl ether, polyoxyl 40 stearate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate,sorbitan monolaureate, sorbitan monooleate, sorbitan monopalmitate,sorbitan monostearate, tyloxapol). This list is not meant to beexclusive, but instead merely representative of the classes ofexcipients and the particular excipients which may be used in dosageforms of the present invention.

The compounds of the invention can form salts which are also within thescope of this invention. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof a disclosed Formula contains both a basic moiety, such as, but notlimited to a pyridine or imidazole, and an acidic moiety, such as, butnot limited to a carboxylic acid, zwitterions (“inner salts”) may beformed and are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful.Salts of the compounds of the invention may be formed, for example, byreacting a compound of the invention with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of the invention, and salts, solvates, esters and prodrugsthereof may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of the invention incorporates a double bond or a fusedring, both the cis- and trans-forms, as well as mixtures, are embracedwithin the scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labelled compounds of the invention (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Benefits of the present invention include oral administration of anoptimal amount of a nicotinamide phosphoribosyltransferase biosynthesisinhibitor.

Benefits of the present invention include intravenous administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include intraperitoneal administrationof an optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include intramural administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include intramuscular administrationof an optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include subcutaneous administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include intra-tumor administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include intrathecal administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Benefits of the present invention include subdural administration of anoptimal amount of a nicotinamide phosphoribosyltransferase biosynthesisinhibitor.

Benefits of the present invention include periorbital administration ofan optimal amount of a nicotinamide phosphoribosyltransferasebiosynthesis inhibitor.

Based on these results, the present invention has important implicationsfor the design of novel treatment strategies for patients with cancer,including leukemias and solid tumors, inflammatory diseases,osteoporosis, atherosclerosis; irritable bowel syndrome and otherconditions disclosed herein or that are known to those skilled in theart.

DESCRIPTION OF CERTAIN EMBODIMENTS

An aspect of the present invention concerns compounds disclosed herein.

An aspect of the present invention concerns compounds which are or canbe inhibitors of the formation of nicotinamidephosphoribosyltransferase.

An aspect of the present invention concerns the use of an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment, prevention,inhibition or elimination of tumors.

An aspect of the present invention concerns the use of an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment, prevention,inhibition or elimination of cancer.

An aspect of the present invention concerns the use of an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment, prevention,inhibition or elimination of cancer, where the cancer is selected fromleukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, coloncancer, cervical cancer, lung cancer, prostate cancer, skin cancer, CNScancer, bladder cancer, pancreatic cancer and Hodgkin's disease.

The present invention also describes one or more methods of synthesizingthe compounds of the present invention.

The invention also describes one or more uses of the compounds of thepresent invention.

The invention also describes one or more uses of the compounds of thepresent invention with an adjunctive agent such as use with TNF, GCSF,or other chemotherapeutic agents.

The invention also describes one or more uses of the pharmaceuticalcompositions of the present invention.

An aspect of the present invention concerns the use as an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment of inflammatorydiseases.

An aspect of the present invention concerns the use as an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment of inflammatorydiseases, such as Irritable Bowel Syndrome or Inflammatory BowelDisease.

An aspect of the present invention concerns the use as an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment of disease of the bonesuch as osteoporosis.

An aspect of the present invention concerns the use as an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment of disease of thecardiovascular system, such as atherosclerosis.

An aspect of the present invention concerns the use as an inhibitor ofthe formation of nicotinamide phosphoribosyltransferase for thepreparation of a medicament used in the treatment of disease or acondition caused by an elevated level of NAMPT.

Such disease or condition is one or more selected from the groupconsisting of cancer, ovarian cancer, breast cancer, uterine cancer,colon cancer, cervical cancer, lung cancer, prostate cancer, skincancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin'sdisease, viral infections, Human Immunodeficiency Virus, hepatitisvirus, herpes virus, herpes simplex, inflammatory disorders, irritablebowel syndrome, inflammatory bowel disease, rheumatoid arthritis,asthma, chronic obstructive pulmonary disease, osteoarthritis,osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupuserythematosis, multiple sclerosis, psoriatic arthritis, ankylosingspodylitis, graft-versus-host disease, Alzheimer's disease,cerebrovascular accident, atherosclerosis, diabetes,glomerulonephiritis, metabolic syndrome, non-small cell lung cancer,small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamouscell cancers, kidney cancer, uretral and bladder cancers, cancers ofhead and neck, cancers of the brain and central nervous system (CNS).

The inventive compounds of can be useful in the therapy of proliferativediseases such as cancer, autoimmune diseases, viral diseases, fungaldiseases, neurological/neurodegenerative disorders, arthritis,inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal,alopecia and cardiovascular disease. More specifically, the compoundscan be useful in the treatment of a variety of cancers, including (butnot limited to) the following: carcinoma, including that of the bladder,breast, colon, kidney, liver, lung, including small cell lung cancer,non-small cell lung cancer, head and neck, esophagus, gall bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, includingsquamous cell carcinoma; hematopoietic tumors of lymphoid lineage,including leukemia, acute lymphocytic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma,non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma,myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia; tumors ofmesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumorsof the central and peripheral nervous system, including astrocytoma,neuroblastoma, glioma and schwannomas; and other tumors, includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma.

The compounds of the invention may induce or inhibit apoptosis.

The compounds of the invention may also be useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse.

A further aspect of the invention is a method of inhibiting a NAMPTpathway in an animal, said method comprising administering to saidanimal a pharmaceutically acceptable amount of a compound of theinvention to an animal in need thereof.

A further aspect of the invention is a pharmaceutical formulationcomprising a compound of the invention.

Another embodiment of the invention comprises a pharmaceuticalformulation of the invention, wherein the pharmaceutical formulation,upon administration to a human, results in a decrease in tumor burden.

Still another embodiment of the invention is a pharmaceuticalformulation, further comprising one or more of an antineoplastic agent,a chemotherapeutic agent, or an adjunctive chemotherapeutic agent.

The pharmaceutical formulations of the invention may further comprise atherapeutic effective amount of an adjunctive chemotherapeutic agent.

The adjunctive chemotherapeutic agent may be an agent, which modifiesblood cell growth and maturation. Non-limiting examples of adjunctivechemotherapeutic agent are filgrastim, pegfilgrastim and erythropoietin.

The invention is also directed to a method of treating or preventing adisorder associated with excessive rate of growth of cells in a mammalcomprising administering to the mammal an effective amount of thepharmaceutical formulation of the invention. Non-limiting examples ofdisorder include cancer or metastasis from malignant tumors.

Another aspect of the invention is a method of inhibiting tumor cellgrowth and rate of division in a mammal with cancer, or other disorderassociated with abnormally dividing cells comprising administering tothe mammal an effective amount of the pharmaceutical formulation of thisinvention.

Another embodiment of the invention is a method of treating bone paindue to excessive growth of a tumor or metastasis to bone in a mammal inneed thereof comprising administering to the mammal an effective amountof the pharmaceutical formulation of this invention.

Still another embodiment of the invention is a method for administeringa NAMPT-inhibitor-containing compound to a mammal in need thereofcomprising administering to the mammal the pharmaceutical formulation ofthe invention. In one embodiment, the mammal is a human.

A further embodiment of the invention is a method of preparing apharmaceutical formulation comprising mixing at least onepharmaceutically acceptable compound of the present invention, and,optionally, one or more pharmaceutically acceptable excipients oradditives.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of the invention and a cell rescuing agent. In anembodiment of the invention, the cell rescuing agent can be selectedfrom the group consisting of nicotinamide, nicotinic acid andnicotinamide mononucleotide.

The invention is also directed to methods of synthesizing compounds ofthe present invention.

Compounds of the Invention

The present invention relates to particular molecules andpharmaceutically acceptable salts or isomers thereof. The inventionfurther relates to molecules which are useful in inhibiting the enzymenicotinamide phosphoribosyltransferase (NAMPT) and pharmaceuticallyacceptable salts or isomers thereof.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts or isomers thereof, and pharmaceuticalcompositions comprising one or more compounds as described herein andpharmaceutically acceptable salts or isomers thereof. One aspect of thisinvention is the provision of compounds, compositions, kits, andantidotes for the NAMPT pathway in mammals having a compound of theFormula I:

wherein

-   R is aryl or heteroaryl, wherein the heteroatom of said heteroaryl    numbers 1, 2 or 3, and is independently selected from N, S or O,    further wherein each of said aryl and heteroaryl may independently    be either substituted or fused with an aryl or heteroaryl, still    further wherein any of said aryl and heteroaryl is either    unsubstituted or optionally independently substituted with one or    more substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),    —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl,-alkoxy or    (alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the    proviso that no two adjacent ring heteroatoms are both S or both O;-   Ar is aryl or heteroaryl, each of said aryl and heteroaryl being    either unsubstituted or optionally independently substituted with 1,    2, 3 or 4 substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),    —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy,    (alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl,    -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl;-   R¹ is cycloalkyl, —CH_(z)F_(3-z), aryl, heterocycloalkyl,    heteroaryl, alkyl, -alkenyl, -alkynyl, (aryl)alkyl-,    (heteroaryl)alkyl- or (heterocycloalkyl)alkyl-, (i) wherein each of    said cycloalkyl, aryl, heterocycloalkyl, heteroaryl and alkyl is    either unsubstituted or optionally substituted with 1, 2, 3, 4 or 5    substituents which can be the same or different and are    independently selected from the group consisting of deuterium, halo,    cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),    —C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),    —OCH_(z)F_(3-z), -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-,    (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl,    (heterocycloalkyl)alkyl-, -aryl, (aryl)alkyl-, -heteroaryl,    (heteroaryl)alkyl-, —S(O)₂-alkyl, —S(O)₂-aryl, —S(O)₂—CF₃,    —C(O)N(alkyl)₂, —C(O)alkyl, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl,    —S(O₂)NH₂, —S(O₂)NH(alkyl), —S(O₂)N(alkyl)₂, —N(H)S(O₂)(alkyl),    —C(O)N(H)(alkyl), and methylenedioxy, (ii) further wherein each of    said cycloalkyl, aryl, heterocycloalkyl, and heteroaryl may    optionally additionally be fused with independently selected aryl,    heteroaryl, heterocycloalkyl or cycloalkyl;-   R³ is H, alkyl or arylalkyl-;-   X is S, S(O), S(O)₂, S(O)₂NH, O or C(O);-   n is 0,1, 2, 3 or 4;-   m is 0, 1, 2, 3 or 4;-   t is 0, 1 or 2; and-   z is 0, 1 or 2;    and pharmaceutically acceptable salts, solates, esters, prodrugs and    isomers thereof.

Another embodiment of the invention are compounds of Formula I, where Ris heteroaryl, wherein the heteroatom of said heteroaryl numbers 1, 2 or3, and is independently selected from N, S or O, further wherein saidheteroaryl may independently be either substituted or fused with an arylor heteroaryl, still further wherein said heteroaryl is eitherunsubstituted or optionally independently substituted with one or moresubstituents which can be the same or different and are independentlyselected from the group consisting of deuterium, halo, cyano, amino,aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂,—C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl,-alkenyl, -alkynyl,-alkoxy or (alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl,—N(R³)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and-heteroaryl, with the proviso that no two adjacent ring heteroatoms areboth S or both O;

Ar is aryl, wherein said is either unsubstituted or optionallyindependently substituted with 1, 2, 3 or 4 substituents which can bethe same or different and are independently selected from the groupconsisting of deuterium, halo, cyano, amino, aminoalkyl-,(amino)alkoxy-, —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),—C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl, -alkenyl,-alkynyl, -alkoxy, (alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl,—N(R³)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and-heteroaryl;

-   R¹ is aryl, heterocycloalkyl or heteroaryl, (i) wherein each of said    aryl, heterocycloalkyl and heteroaryl is either unsubstituted or    optionally substituted with 1, 2, 3, 4 or 5 substituents which can    be the same or different and are independently selected from the    group consisting of deuterium, halo, cyano, amino, aminoalkyl-,    (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂,    —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z),    -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-,    -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl,    (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O)₂-alkyl,    —S(O)₂-aryl, —S(O)₂—CF₃, —C(O)N(alkyl)₂, —C(O)alkyl,    —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl, —S(O₂)NH₂, —S(O₂)NH(alkyl),    —S(O₂)N(alkyl)₂, —N(H)S(O₂)(alkyl), —C(O)N(H)(alkyl), and    methylenedioxy, (ii) further wherein each of said cycloalkyl, aryl,    heterocycloalkyl, and heteroaryl may optionally additionally be    fused with independently selected aryl, heteroaryl, heterocycloalkyl    or cycloalkyl; R³ is H, alkyl or arylalkyl-;    And X, n, m, q, t, and z are defined as above.

In the compounds of Formula I, the various moieties are independentlyselected.

The following embodiments are directed to Formula I as applicable. Forany moieties that are not specifically defined, the previous definitionscontrol. Further, the moieties aryl, heteroaryl, and heterocycloalkyl inthese embodiments can be independently unsubstituted or optionallysubstituted or optionally fused as described earlier. Any one or more ofthe embodiments of Formula I below may be combined with one or moreother embodiments of Formula I.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is aryl, andn, m, q, t, z, Ar, X, R¹ and R³ are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isheteroaryl, and n, m, q, t, z, Ar, X, R¹ and R³ are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar is aryl,and R, n, m, q, t, z, X, R¹ and R³ are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar isheteroaryl, and R, n, m, q, t, z, X, R¹ and R³ are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is S.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is S(O).

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is S(O₂).

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is O.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is C(O).

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and R³ are as defined and X is C(O).

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and X are as defined and R³ is H.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and X are as defined and R³ is alkyl.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R¹ and X are as defined and R³ is arylalkyl.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R³ and X are as defined and R¹ is aryl.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R³ and X are as defined and R¹ is heteroaryl.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, Ar, R, n, m,q, t, z, R³ and X are as defined and R¹ is heterocycloalkyl.

An embodiment of the invention is the provision of a compound, where thevarious moieties are independently selected, R is aryl, R¹ isheteroaryl, and n, m, q, t, z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is aryl, R¹is aryl, and n, m, q, t, z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isheteroaryl, R¹ is heteroaryl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isheteroaryl, R¹ is aryl, and n, m, q, t, z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is phenyl,R¹ is heteroaryl, and n, m, q, t, z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is phenyl,R¹ is aryl, and n, m, q, t, R¹, R³ z, and Ar are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isheteroaryl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrrolopyridinyl, R¹ is phenyl, and n, m, q, t, Ar, z, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl, R¹ is phenyl, and n, m, q, t, Ar, z, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl (substituted with pyridinyl), R¹ is phenyl, and n, m, q, t,z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrazolyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is pyrazolyl(substituted with pyridinyl), R¹ is phenyl, and n, m, q, t, z, Ar, R³and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazolyl, R¹ is phenyl, and n, m, q, t, Ar, z, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istriazolopyridinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isnaphthyridinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istetrazolopyridinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isisoquinolinyl, R¹ is phenyl, and n, m, q, t, Ar, R³ z, and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinolinyl, R¹ is phenyl, and n, m, q, t, Ar, z, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazopyrazinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinazolinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isbenzothiazolyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isthienopyridinyl, R¹ is phenyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrrolopyridinyl, R¹ is thiophenyl, and n, m, q, z, t, Ar, R³ and X areas defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl, R¹ is naphthalinyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl (substituted with pyridinyl), R¹ is quinolinyl, and n, m, q,z, t, Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrazolyl, R¹ is isoquinolinyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is pyrazolyl(substituted with pyridinyl), R¹ is benzodioxinyl, and n, m, q, t, z,Ar, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazolyl, R¹ is phenoxathiinyl, and n, m, q, t, z, Ar, R³ and X are asdefined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrrolopyridinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ andX are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and X areas defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl (substituted with pyridinyl), R¹ is phenyl, Ar is phenyl,and n, m, z, q, t, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrazolyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and X areas defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is pyrazolyl(substituted with pyridinyl), R¹ is phenyl, Ar is phenyl, and n, m, q,z, t, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazolyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and X areas defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istriazolopyridinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ andX are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isnaphthyridinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and Xare as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istetrazolopyridinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isisoquinolinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and Xare as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinolinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and X areas defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazopyrazinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ andX are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinazolinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and Xare as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isbenzothiazolyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and Xare as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isthienopyridinyl, R¹ is phenyl, Ar is phenyl, and n, m, q, t, z, R³ and Xare as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrrolopyridinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, tis 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is 0,z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isoxadiazolyl (substituted with pyridinyl), R¹ is phenyl, Ar is phenyl, nis 1, m is 1, q is 0, t is 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R ispyrazolyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is 0, zis 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R is pyrazolyl(substituted with pyridinyl), R¹ is phenyl, Ar is phenyl, n is 1, m is1, q is 0, t is 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazolyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is 0,z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istriazolopyridinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, tis 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isnaphthyridinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R istetrazolopyridinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0,t is 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isisoquinolinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinolinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is 0,z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isimidazopyrazinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, tis 0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isquinazolinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compound of FormulaI, where the various moieties are independently selected, R isbenzothiazolyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, t is0, z is 0, R³ and X are as defined.

An embodiment of the invention is the provision of a compounds ofFormula I, where the various moieties are independently selected, R isthienopyridinyl, R¹ is phenyl, Ar is phenyl, n is 1, m is 1, q is 0, tis 0, z is 0, R³ and X are as defined.

Embodiments of the invention of Formula I include any combinations ofthe embodiments described above for Formula I.

Another embodiment of the invention is compounds of Formula I, whereX═SO₂, n=1, m=0 and t=0, whereby the formula becomes Formula IA:

R, Ar, and R₁ are defined as in Formula I above.

Another aspect of the invention is compounds of Formula IA where R ispyridine and the Formula becomes Formula IB:

wherein:

-   Ar is aryl or heteroaryl, each of said aryl and heteroaryl being    either unsubstituted or optionally independently substituted with 1,    2, 3 or 4 substituents which can be the same or different and are    independently selected from the group consisting of:    -   deuterium, halo, cyano, amino, aminoalkyl-, (amino)alkoxy-,        —CONH₂, —C(O)NH(alkyl), —C(O)N(alkyl)₂, —C(O)NH(aryl),        —C(O)N(aryl)₂, —CH_(z)F_(3-z), —OCH_(z)F_(3-z), -alkyl,        -alkenyl, -alkynyl, -alkoxy, (alkoxyalkyl)amino-,        —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl, -cycloalkyl,        -heterocycloalkyl, -aryl, and -heteroaryl;-   R¹ is —NR^(a)R^(b), wherein R^(a) is H, alkyl or —S(O)₂alkyl and    R^(b) is alkyl, hydroxyalkyl, —S(O)₂alkyl, —(CH₂)_(q)cycloalkyl,    —(CH₂)_(q)heterocycloalkyl, aryl, arylalkyl-, —(CH₂)_(q)heteroaryl;    -   cycloalkyl;    -   aryl;    -   heterocycloalkyl;    -   heteroaryl;        -   each of said cycloalkyl, aryl, or heteroaryl is            unsubstituted or substituted with 1, 2, 3, 4 or 5            substituents which can be the same or different and are            independently selected from the group consisting of:            -   deuterium, halo, cyano, alkyl, hydroxyl, hydroxyalkyl,                hydroxyalkoxy, cyanoalkyl, haloalkyl, alkenyl, alkynyl,                alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy,                benzyloxy, oxo, —(CH₂)_(q)—NR^(c)R^(d),                —(CH₂)_(q)—CONR^(c)R^(d), —S(O)₂-alkyl, —S(O)₂-aryl,                S(O)₂NH₂, —S(O)₂NH-alkyl, —S(O)₂N(alkyl)₂,                —S(O)₂-heterocycloalkyl, —S(O)₂—CF₃, —C(O)alkyl,                —C(O)aryl, —C(O)alkylenylaryl, —C(O)O-alkyl,                —NH—C(O)alkyl, —NH—C(O)aryl, methylenedioxy,                —(CH₂)_(q)cycloalkyl, cycloalkylalkoxy-, aryl,                arylalkyl-, —(CH₂)_(q)heteroaryl, and                —(CH₂)_(q)heterocycloalkyl,            -   wherein each of said cycloalkyl, heterocycloalkyl, aryl                or heteroaryl may be substituted by one or more halo,                nitro, haloalkyl, haloalkoxy, oxo, cyano, alkyl,                haloalkyl, or alkoxy and;-   R^(c) and R^(d) are independently selected from the group consisting    of H, alkyl, hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, —S(O)₂alkyl    and cycloalkyl or R^(c) and R^(d) can form a 5 or 6 membered    heterocycloalkyl group together with the nitrogen atom to which they    are attached, wherein said heterocycloalkyl group may contain one or    more additional heteroatom(s) selected from N, S or O;-   and pharmaceutically acceptable salts thereof, with the proviso that    the compound of formula Ia is not:-   N-[3-(cyclopentylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[2-(1-methylethoxy)-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[2-ethoxy-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[5-[(hexahydro-1Hazepin-1-yl)sulfonyl]-2-(2,2,2-trifluoroethoxy)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[5-[(diethylamino)sulfonyl]-2-(4-morpholinyl)phenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[3-[[(3-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;-   N-[3-[[(4-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;-   3-(3-pyridinyl)-N-[4-[[(tetrahydro-1,1-dioxido-3-thienyl)amino]sulfonyl]phenyl]-2-propenamide;-   3-(3-pyridinyl)-N-[3-[[[3-(trifluoromethyl)phenyl]amino]sulfonyl]phenyl]-2-propenamide;    and-   3-(3-pyridinyl)-N-[1,4,5,6-tetrahydro-5-[(4-methylphenyl)sulfonyl]pyrrolo[3,4-c]pyrazol-3-yl]-2-propenamide.

Another embodiment of Formula BI is compounds, wherein Ar is aryl.

Another embodiment of the invention is compounds of Formula IB where Aris Phenyl and the Formula becomes Formula IC:

wherein:

-   R¹ is —NR^(a)R^(b), wherein R^(a) is H, R^(b) is unsubstituted or    substituted aryl;    -   aryl,    -   heterocycloalkyl;    -   heteroaryl;        -   each of said cycloalkyl, aryl, or heteroaryl is            unsubstituted or substituted with 1, 2, 3, 4 or 5            substituents which can be the same or different and are            independently selected from the group consisting of:            -   halo, alkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy,                —C(O)NR^(c)R^(d), heteroaryl (pyrazol), heterocycloalkyl                (morpholine), aryl, —NHS(O)₂alkyl, —S(O)₂alkyl and                —S(O)₂NH₂;-   R^(c) and R^(d) are independently selected from H, alkyl and    cycloalkyl; and pharmaceutically acceptable salts thereof.

Another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is —NR^(a)R^(b), wherein R^(a) is H, alkyl or —S(O)₂alkyl andR^(b) is alkyl, hydroxyalkyl, —S(O)₂alkyl, —(CH₂)_(q)cycloalkyl,—(CH₂)_(q)heterocycloalkyl, aryl, arylalkyl- or —(CH₂)_(q)heteroaryl.

Still another embodiment of the invention is compounds of Formula IB orIC, where R¹ is —NR^(a)R^(b), wherein R^(a) is H, C₁-C₆-alkyl or—S(O)₂—C₁-C₆-alkyl and R^(b) is C₁-C₆-alkyl, hydroxy C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, —(CH₂)_(q)—C₃-C₆-cycloalkyl,—(CH₂)_(q)heterocycloalkyl, phenyl, phenylalkyl- or—(CH₂)_(q)heteroaryl, wherein heterocycloalkyl groups are 5 or 6membered heterocycloalkyl groups containing 1, 2 or 3 heteroatomsselected from the group consisting of N, O and S and wherein heteroarylgroups are 5 or 6 membered heteroaryl groups containing 1, 2 or 3heteroatoms selected from the group consisting of N, O and S.

Yet another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is cycloalkyl.

Another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is C₃-C₆-cycloalkyl.

Another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is aryl

Another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is naphthalene.

Another embodiment of the invention are compounds of Formula IB or ICwhere R¹ is heterocycloalkyl.

Another embodiment of the invention are compounds of Formula IB or ICwhere R¹ is 5 or 6 membered heterocycloalkyl groups containing 1, 2 or 3heteroatoms selected from the group consisting of N, O and S.

Another embodiment of the invention are compounds of Formula IB or ICwhere R¹ is selected from the group consisting of: pyrrolidin,piperidin, and 8-oxa-3-azabicyclo[3.2.1]octane.

Another embodiment of the invention is compounds of Formula IB or ICwhere R¹ is heteroaryl.

Another embodiment of the invention are compounds of Formula IB or ICwhere R¹ is 5 or 6 membered heteroaryl groups containing 1, 2 or 3heteroatoms selected from the group consisting of N, O and S.

Another embodiment of the invention are compounds of Formula IB or ICwhere R¹ is elected from the group consisting of: pyridine, pyrazole,thiophene, pyrimidine, 1H-indole, quinoline, isoquinoline, 1H-indazole,benzothiophene, phenoxathiine, 2H-1,3-benzodioxole,2,3-dihydro-1-benzofuran, and 8-oxatricyclo[7.40.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene.

Another embodiment of the invention are compounds of Formula IB or ICwhere for R¹, each of said cycloalkyl, aryl, or heteroaryl isunsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which canbe the same or different and are independently selected from the groupconsisting of:

deuterium, halo, cyano, C₁-C₆-alkyl, hydroxyl, hydroxy-C₁-C₆-alkyl,hydroxyl-C₁-C₆-alkoxy, cyano-C₁-C₆-alkyl, halo-C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy, C₁-C₆-alkyl-C₁-C₆-alkoxy,halo-C₁-C₆-alkoxy, aryl-C₂-C₆-alkenyl-, aryloxy, benzyloxy, oxo,—(CH₂)_(q)—NR^(c)R^(d), —(CH₂)_(q)—CONR^(c)R^(d), —S(O)₂—C₁-C₆-alkyl,—S(O)₂-aryl, S(O)₂NH₂, —S(O)₂NH—C₁-C₆-alkyl, —S(O)₂N(C₁-C₆-alkyl)₂,—S(O)₂-heterocycloalkyl, —S(O)₂—CF₃, —C(O)—C₁-C₆-alkyl, —C(O)aryl,—C(O)C₁-C₆-alkylenylaryl, —C(O)O—C₁-C₆-alkyl, —NH—C(O)—C₁-C₆-alkyl,—NH—C(O)aryl, methylenedioxy, —(CH₂)_(q)—C₃-C₆-cycloalkyl,C₃-C₆-cyclo-C₁-C₆-alkyl-C₁-C₆-alkoxy-, aryl, aryl-C₁-C₆-alkyl-,—(CH₂)_(q)heteroaryl, and —(CH₂)_(q)heterocycloalkyl, wherein each ofsaid cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be substitutedby one or more halo, nitro, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, oxo,cyano, —C₁-C₆-alkyl, halo-C₁-C₆-alkyl, or —C₁-C₆-alkoxy and;

R^(c) and R^(d) are independently selected from the group consisting ofH, C₁-C₆-alkyl, hydroxy-C₁-C₆-alkyl, C₁-C₆-alkoxy, aryl,C₁-C₆-alkoxy-C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl and C₃-C₆-cycloalkyl orR^(c) and R^(d) can form a 5 or 6 membered heterocycloalkyl grouptogether with the nitrogen atom to which they are attached, wherein saidheterocycloalkyl group may contain one or more additional heteroatom(s)selected from N, S or O.

Another embodiment of the invention is compounds of Formula IB or IC

where R¹ is selected from the group consisting of:

-   (1H-pyrazol-1-yl)benzene; 1-benzothiophene; 1H-indole;    1-methyl-1H-indazole; 1-methyl-1H-indole; 1-methyl-1H-pyrazole;    2-(dimethylamino)pyrimidine; 2-(morpholin-4-yl)pyridine;    2-(trifluoromethoxy)benzene; 2,3-dihydro-1-benzofuran;    2,5-dichlorobenzene; 2-chloro-5-(trifluoromethoxy)benzene;    2H-1,3-benzodioxole; 2-methoxy-4-(trifluoromethyl)benzene;    2-methoxy-5-(propan-2-yl)benzene;    2-methoxy-5-(trifluoromethoxy)benzene;    2-methoxy-5-(trifluoromethyl)benzene; 2-methoxy-5-methylbenzene;    2-methoxybenzene; 2-methyl-4-(trifluoromethyl)benzene;    2-methylbenzene; 3-(2-methylpropoxy)benzene;    3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene; 3-(ethanesulfonyl)benzene;    3-(methoxymethyl)benzene; 3-(morpholin-4-yl)benzene;    3-(propan-2-yloxy)benzene; 3-(trifluoromethoxy)benzene;    3-(trifluoromethyl)benzene; 3,4-dichlorobenzene;    3,4-dimethoxybenzene; 3,5-dichlorobenzene; 3,5-dimethoxybenzene;    3,5-dimethylbenzene; 3-chloro-4-(trifluoromethyl)benzene;    3-chloro-4-methoxybenzene; 3-chloro-4-methylbenzene;    3-chloro-4-propoxybenzene; 3-chloro-5-(trifluoromethyl)benzene;    3-chloro-5-fluorobenzene; 3-chloro-5-methoxybenzene;    3-chloro-5-methylbenzene; 3-chlorobenzene;    3-ethanesulfonamidobenzene; 3-ethoxybenzene; 3-ethylbenzene;    3-fluoro-4-methoxybenzene; 3-fluoro-4-methylbenzene;    3-fluoro-4-propoxybenzene; 3-fluoro-5-(2-methylpropoxy)benzene;    3-fluoro-5-methoxybenzene); 3-fluoro-5-methylbenzene;    3-fluorobenzene; 3-methanesulfonamidobenzene;    3-methanesulfonylbenzene; 3-methoxybenzene; 3-methylbenzene;    3-phenylbenzene; 3-propoxybenzene; 4-(1-methyl-1H-indazole;    4-(2-methylpyridine; 4-(ethoxymethyl)benzene;    4-(morpholin-4-yl)benzene; 4-(propan-2-yloxy)benzene;    4-(trifluoromethoxy)benzene; 4-(trifluoromethyl)benzene;    4-chloro-2-ethoxybenzene; 4-chloro-2-methoxybenzene;    4-chloro-3-(trifluoromethyl)benzene; 4-chloro-3-methoxybenzene;    4-chlorobenzene; 4-ethoxy-3-fluorobenzene; 4-ethoxybenzene;    4-fluoro-3-methylbenzene; 4-fluorobenzene; 4-methanesulfonylbenzene;    4-methoxy-3,5-dimethylbenzene; 4-methoxy-3-methylbenzene;    4-methylpyridine; 4-phenylbenzene; 5-(pyrrolidin-1-yl)pyridine;    5-chloro-2-ethoxybenzene; 5-chloro-2-methoxybenzene;    5-fluoro-2-methoxybenzene; 5-fluoro-2-methylbenzene;    5-methoxypyridine; 5-methylpyridine; 5-methylthiophene;    6-(dimethylamino)pyridine; 6-methoxynaphthalene; 6-methylpyridine;    8-oxa-3-azabicyclo[3.2.1]octane;    8-oxatricyclo[7.4.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene;    isoquinoline; morpholin-4-yl; naphthalene; phenoxathiine; phenyl;    pyridin-3-yl; pyridine; and quinoline.

Any one or more of the aforementioned embodiments for Formulas IB and ICmay be combined to form additional embodiments.

In another embodiment, the invention is further illustrated by thecompounds shown in Table 2.

TABLE 2 Structure Chemical Name

(2E)-N-(4-{[3-fluoro-5-(2- methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-fluoro-4- propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(phenoxathiine-4- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(2,5- dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

N-ethyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2E)-N-[4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-[4-(2,3-dihydro-1-benzofuran-7-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(4-fluoro-3- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(2- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(2-methylpyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[4-(1H-pyrazol-1- yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(naphthalene-1-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-fluoro-4- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4- chlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

N-ethyl-4-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2E)-N-{4-[(3-chloro-4- propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3-(1H-pyrazol-1- yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(5-chloro-2- ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-methyl-1H-indazole-6-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(3-chloro-4- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-(4-{[4-(trifluoromethyl)benzene]sulfonyl}phenyl) prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-(4-{[3-(trifluoromethoxy)benzene]sulfonyl}phenyl) prop-2-enamide

(2E)-N-(4-{[2-methoxy-5-(propan-2-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3- yl)prop-2-enamide

(2E)-N-[4-(1H-indole-7-sulfonyl)phenyl]-3- (pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-{4-[5-(pyrrolidin-1-yl)pyridine-3-sulfonyl]phenyl}prop-2- enamide

(2E)-N-(4-{[3-chloro-5- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-methyl-1H-indole-2-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-3-(pyridin-3-yl)-N-(4-{[4-(trifluoromethoxy)benzene]sulfonyl}phenyl) prop-2-enamide

(2E)-N-{4-[(3-chloro-4- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(6-methoxynaphthalene-2-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(4-ethoxy-3- fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-fluoro-5- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3,4- dimethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[4-(morpholin-4-yl)piperidine-1-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide

(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-3- sulfonyl)phenyl]prop-2-enamide

(2E)-N-(4-{[2-chloro-5- (trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4- benzene)sulfonyl]phenyl}-3-(pyridin- 3-yl)prop-2-enamide

(2E)-N-{4-[(3- fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3,5- dimethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(5-methoxypyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- chlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-chloro-5- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- methanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(5-methylpyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3- (methoxymethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[(4-{8-oxa-3- azabicyclo[3.2.1]octane-3-sulfonyl}phenyl)methyl]-3-(pyridin-3- yl)prop-2-enamide

(2E)-N-{4-[(3,5- dimethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(5-fluoro-2- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-(4-{[2-(trifluoromethoxy)phenyl]sulfamoyl}phenyl) prop-2-enamide

(2E)-N-[4-(6-methylpyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(isoquinoline-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

3-chloro-N,N-diethyl-5-({4-[(2E)-3- (pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2E)-N-{4-[(4-methoxy-3- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(benzenesulfonyl)phenyl]-3- (pyridin-3-yl)prop-2-enamide

N-cyclopentyl-3-({4-[(2E)-3-(pyridin-3- yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2E)-N-{4-[(3- methanesulfonylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[2-(morpholin-4-yl)pyridine-3-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide

(2E)-3-(pyridin-3-yl)-N-(4-{[2-(trifluoromethoxy)benzene]sulfonyl}phenyl) prop-2-enamide

N-(propan-2-yl)-3-({4-[(2E)-3-(pyridin-3- yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2E)-3-(pyridin-3-yl)-N-(4-{[3-(trifluoromethyl)benzene]sulfonyl}phenyl) prop-2-enamide

(2E)-N-[4-(1-benzothiophene-7- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[2-(dimethylamino)pyrimidine-5-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(4- ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-fluoro-4- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1H-indole-4-sulfonyl)phenyl]-3- (pyridin-3-yl)prop-2-enamide

(2E)-N-{[4- (benzenesulfonyl)phenyl]methyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-8- sulfonyl)phenyl]prop-2-enamide

(2E)-N-(4-{[2-methoxy-5- (trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(5-methylthiophene-2- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4-chloro-3- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[2-methoxy-4- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

N-(2-methylpropyl)-3-({4-[(2E)-3-(pyridin- 3-yl)prop-2-enamido]benzene}sulfonyl)benzamide

N-cyclopropyl-3-({4-[(2E)-3-(pyridin-3- yl)prop-2-enamido]benzene}sulfonyl)benzamide

(2Z)-N-[4-(benzenesulfonyl)phenyl]-2-fluoro-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-fluoro-5- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[2-methyl-4- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-propyl-1H-pyrazole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-(4-{[4- (ethoxymethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4- methanesulfonylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4-methoxy-3,5- dimethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(5-chloro-2- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[4-(morpholin-4- yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-[4-(pyridine-3- sulfonyl)phenyl]prop-2-enamide

(2E)-N-(4-{[3-(propan-2- yloxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4-chloro-2- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3-(2- methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- ethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-6- sulfonyl)phenyl]prop-2-enamide

(2E)-N-{4-[(3-chloro-5- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(2-methoxy-5- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3,5- dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3-(morpholin-4- yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3- yl)prop-2-enamide

(2E)-N-{4-[(3- propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{8-oxatricyclo[7.4.0.0²,⁷]trideca- 1(13),2,4,6,9,11-hexaene-6-sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(5-fluoro-2- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-methyl-1H-indazole-5-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-(4-{[4-(propan-2- yloxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3-chloro-4- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-3-(pyridin-3-yl)-N-{4-[(3- sulfamoylbenzene)sulfonyl]phenyl}prop-2-enamide

(2E)-N-{4-[(3- methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(2- methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(2H-1,3-benzodioxole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(3- ethanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4- fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(4-methylpyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-methyl-1H-indazole-7-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-{4-[(3,4- dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-[4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2- enamide

(2E)-N-(4-{[4-chloro-3- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[2-methoxy-5- (trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-(4-{[3- (ethanesulfonyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3-chloro-5- fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(4-chloro-2- ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[(3- phenylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide

(2E)-N-{4-[6-(dimethylamino)pyridine-3-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide

EXAMPLES

The following are illustrative, but non-limiting, examples of certainembodiments of the present invention. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present inventions, asdemonstrated by the following examples. Unless otherwise specified, allregents and solvents are of standard commercial grade and are usedwithout further purification.

Definitions used in the following Schemes and elsewhere herein are:

-   BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate-   CDCl₃ deuterated chloroform-   δ chemical shift (ppm)-   DCM dichloromethane or methylene chloride-   DIEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ deuterated dimethylsulfoxide-   EDCI N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine    hydrochloride-   EtOAc ethyl acetate-   EtOH ethanol-   GF/F glass microfiber filter-   ¹H NMR proton nuclear magnetic resonance-   HOAc acetic acid-   HATU    2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate-   HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate-   HPLC high pressure liquid chromatography-   MHz megahertz-   KOAc potassium acetate-   i-PrOH isopropanol-   LC-MS liquid chromatography/mass spectrometry-   (M+1) mass+1-   m-CPBA m-chloroperbenzoic acid-   MeOH methanol-   N₂ nitrogen-   NaHCO₃ sodium bicarbonate-   MgSO₄ magnesium sulfate-   PTLC preparative thin layer chromatography-   TEA triethylamine-   THF tetrahydrofuran-   TLC thin layer chromatography    Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention amide-sulfone (III) can be synthesized by followingthe steps outlined in Scheme 1.

Compound III can be obtained by treating I with II (X═OH) in thepresence of a coupling reagent such as EDCI, HATU, BOP, or HOBt, and abase (eg: K₂CO₃, Cs₂CO₃, NR₁R₂R₃, NaOR, KOR) or a base (X═Cl) such asK₂CO₃, Cs₂CO₃, NR₁R₂R₃, NaOR, KOR in an inert solvent such asdichloromethane, N,N-dialkylformamide, N,N-dialkylacetamide,dialkylethers, DMSO, or N-methyl-2-pyrrolidinone at temperatures rangingfrom −78° C. to 200° C.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them. Those having skill in the artwill recognize that the starting materials may be varied and additionalsteps employed to produce compounds encompassed by the presentinventions, as demonstrated by the following examples. In some cases,protection of certain reactive functionalities may be necessary toachieve some of the above transformations. In general, such need forprotecting groups, as well as the conditions necessary to attach andremove such groups, will be apparent to those skilled in the art oforganic synthesis.

Preparation of Representative Aza-Cinnamide Analogues

These examples illustrate the preparation of representative substitutedurea-sulfonamide analogues.

Example 1(Z)-2-fluoro-N-(4-(phenylsulfonyl)phenyl)-3-(pyridin-3-yl)acrylamide

The mixture of (Z)-2-fluoro-3-(pyridin-3-yl)acrylic acid (100 mg, 0.598mmol),4-(phenylsulfonyl)aniline (140 mg, 0.598 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (341 mg, 0.897 mmol), DIEA (232 mg, 1.795 mmol)in DMF (Volume: 10 ml) was stirred at RT for overnight, removed DMF,extracted with EtOAc, washed with 1N NaOH, brine, dried and the biotagepurification afforded the product (51 mg, 23%).

¹HNMR (DMSO-D₆): δ 10.84 (s, 1H), 8.85 (s, 1H), 8.57 (d, 1H), 8.10 (m,1H), 7.95 (m, 6H), 7.64 (m, 3H), 7.50 (m, 1H), 7.20 (d, 1H)

LC-MS: 383.06 (M+1).

Example 2(E)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide

A. 4-(2-(trifluoromethoxy)phenylthio)benzonitrile

To a solution of 2-(trifluoromethoxy)benzenethiol (1.035 g, 5.33 mmol)in DMF (15 mL) at 0° C. was added K₂CO₃ (921 mg, 6.66 mmol). Thesolution was warmed to ambient temperature over 10 min before4-fluorobenzonitrile (613 mg, 5.06 mmol) was added at once. The mixturewas heated to 120° C. for 16 hours, then was then cooled and poured ontoice. The mixture was diluted with EtOAc, the layers separated, and theorganics were washed successively with sat. NaHCO₃ and brine (2×). Theorganics were dried (MgSO4), filtered, and purified by Biotage SP1(DCM/hexanes gradient) to afford4-((2-(trifluoromethoxy)phenyl)thio)benzonitrile (1.098 g, 74%) as agolden oil.

¹H NMR (DMSO-d₆): δ 7.77 (dt, 2H), 7.66-7.54 (m, 3H), 7.52-7.44 (m, 1H),7.32-7.26 (dt, 2H).

B. 4-((2-(trifluoromethoxy)phenyl)sulfonyl)benzonitrile

To a solution of 4-(2-(trifluoromethoxy)phenylthio)benzonitrile (0.88 g,2.98 mmol) in chloroform (25 ml) at 0° C. was added m-CPBA (1.46 g, 6.35mmol) and the solution was warmed to ambient temperature overnight. Themixture was filtered and the solids rinsed with chloroform. The filtratewas washed with 1N NaOH (2×) and the organics were dried (MgSO₄),filtered, and purified by Biotage SP1 (hexanes/CH₂Cl₂ gradient) toafford 4-((2-(trifluoromethoxy)phenyl)sulfonyl)benzonitrile as a whitesolid (900 mg, 92%).

¹H NMR (DMSO-d₆): δ 8.27 (dd, 1H), 8.16-8.11 (d, 2H), 8.08-8.03 (d, 2H),7.93-7.86 (td, 1H), 7.74-7.67 (t, 1H), 7.56 (d, 1H).

C. (4-(2-(Trifluoromethoxy)phenylsulfonyl)phenyl)methanamine

In a 100 mL round-bottomed flask was added4-(2-(trifluoromethoxy)phenylsulfonyl)benzonitrile (900 mg, 2.75 mmol)in THF (Volume: 25 mL) to give a colorless solution. Borane (1 molar inTHF, 6.87 mL, 6.87 mmol) was added and the mixture heated to reflux andmonitored by TLC. TLC appeared to show little reaction after 3 hours, soheated overnight. TLC did not change so added 2 additional equivalentsof borane and refluxed for an additional two hours. The reaction wasthen cooled and slowly quenched with methanol. The reaction was dilutedwith ethyl acetate and poured into a separatory funnel. The organiclayer was washed with 2M NaOH, water, and saturated, aqueous sodiumchloride. The organic was separated, dried with anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to give 927.8mg of crude product. Material purified on Biotage to give 422.0 mg ofproduct (46% yield).

¹H NMR (300 MHz, DMSO-d6): δ 8.24 (dd, 1H), 7.85 (m, 3H), 7.68 (t, 1H),7.59 (d, 2H), 7.53 (m, 1H), 3.79 (s, 2H), 2.05 (br.s, 2H).

LC-MS (ESI): 332.06 (M+1).

D.(E)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide

In a 50 ml of flask were added(4-(2-(trifluoromethoxy)phenylsulfonyl)phenyl)methanamine (100 mg, 0.302mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (138 mg, 0.362 mmol DIEA (117 mg, 0.905 mmol),(E)-3-(pyridin-3-yl)acrylic acid (49.5 mg, 0.332 mmol) DMF (5 ml). Themixture was stirred at RT for 16 hours. The mixture was diluted withwater and back extracted with ethyl acetate (3×20 mL). The organiclayers were combined and washed with water (3×20 mL). The organic wasseparated, dried with anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give the crude product The crudeproduct was purified by Biotage to affordE)-3-(pyridin-3-yl)-N-(4-(2-(trifluoromethoxy)phenylsulfonyl)benzyl)acrylamide,85 mg (61%). ¹HNMR (DMSO-D₆): δ 8.70 (t, 1H), 8.75 (d, 1H), 8.54 (dd,1H), 8.21 (dd, 2H), 7.98 (dd, 1H), 7.83 (m, 2H), 7.66 (dt, 1H), 7.53 (m,2H), 7.44 (m, 1H), 6.75 (d, 1H), 4.49 (d, 1H)

LC-MS: 462.99 (M+1).

Example 3N-(4-((4-methoxyphenyl)sulfonyl)phenyl)-3-(pyridin-3-yl)acrylamide

A. N-(4-((4-methoxyphenyl)sulfonyl)phenyl)acetamide

To a solution of sodium 4-acetamidobenzenesulfinate dehydrate (128 mg,0.5 mmol), 4-methoxy-phenylboronic acid (114 mg, 0.75 mmol) and Et₃N(0.313 mL, 2.25 mmol) in 1,4-dioxane (4 mL) and DMSO (4 mL) is addedCu(OAc)₂ (114 mg, 0.625 mmol). The mixture is heated at 60° C. for 16 hthen cooled to ambient temperature. EtOAc (12 ml) and brine (6 ml) isadded followed by concentrated NH₄OH (0.6 mL) and the mixture is stirredat ambient temperature for 15 min. The layers are separated and theaqueous layer is extracted with EtOAc (6 mL). The combined extracts aredried (Na₂SO₄) and evaporated. The residue is purified by preparativeTLC with 2:1 EtOAc/hexanes to give 111 mg (72%) white solid.

¹HNMR (400 MHz, CDCl₃): δ 8.76 (s, broad, 1H), 7.77-7.81 (m, 4H), 7.66(d, 2H), 6.91-6.93 (m, 2H), 3.81 (s, 3H), 2.13 (s, 3H).

LC_MS: M+1 306.15;

B. 4-((4-methoxyphenyl)sulfonyl)aniline

To a solution of N-(4-((4-methoxyphenyl)sulfonyl)phenyl)acetamide (111mg, 0.36 mmol) in EtOH (8 mL) is added NaOH (10 M in water, 0.6 mL, 6mmol). The mixture is heated at 80° C. for 4 h and the solvent isevaporated. The residue is partitioned between EtOAc (15 mL) and brine(10 mL) and the layers are separated. The aqueous layer is extractedwith EtOAc (10 mL) and the combined extracts are dried (Na₂SO₄) andevaporated. The white solid obtained (76 mg, 80%) is used to the nextstep without further purification.

¹HNMR (400 MHz, CDCl₃): δ 7.79 (d, 2H), 7.64 (d, 2H), 6.91 (d, 2H), 6.61(d, 2H), 4.21 (s, broad, 2H), 3.80 (s, 3H).

LC_MS: M+1 264.11.

C. 3-(pyridin-3-yl)acryloyl chloride hydrochloride

To a suspension of 3-(pyridin-3-yl)acrylic acid (1.03 g, 6.9 mmol) inDCM (25 ml) is added oxalyl chloride (2 M in DCM, 17.25 mL, 34.5 mmol)dropwise. With stir, 100 uL of DMF is added and the mixture is stirredat RT for 30 min then heat at reflux for 3 h. The solvent is removedunder vacuum and ether is added (40 mL). The suspension is stirred at RTfor 30 min then filtered. The solid is washed with ether (20 mL) anddried under vacuum to give the tilted compound as a white solid. (1.22g, 87%).

¹HNMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.84 (d, 1H), 8.79 (d, 1H),7.98 (dd, 1H), 7.77 (d, 1H), 6.90 (d, 1H).

D. N-(4-((4-methoxyphenyl)sulfonyl)phenyl)-3-(pyridin-3-yl)acrylamide

To a solution of 4-((4-methoxyphenyl)sulfonyl)aniline (76 mg, 0.29 mmol)in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (62 mg, 0.30mmol) and K₂CO₃ (138 mg, 1 mmol). The mixture is heated at 50° C. for 2h and the solvent is evaporated. The residue is partitioned betweenEtOAc (15 mL) and brine (10 mL) and the layers are separated. Theaqueous layer is extracted with EtOAc (10 mL) and the combined extractsare dried (Na₂SO₄) and evaporated. Purification of the residue bypreparative TLC with 100:5:0.5 CH₂Cl₂/MeOH/NH₄OH gives the titledcompounds as a white solid (66 mg, 58%).

¹HNMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.81 (d, 1H), 8.57 (dd, 1H),8.03 (d, 1H), 7.88 (s, 4H), 7.84 (d, 2H), 7.65 (d, 1H), 7.46 (dd, 1H),7.10 (d, 2H), 6.90 (d, 1H), 3.80 (s, 3H).

LC_MS: M+1 395.16.

Example 43-(pyridin-3-yl)-N-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)acrylamide

A. N-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)acetamide

To a solution of sodium 4-acetamidobenzenesulfinate dehydrate (128 mg,0.5 mmol), 3-trifluoromethoxy-phenylboronic acid (144 mg, 0.75 mmol) andEt₃N (0.313 mL, 2.25 mmol) in 1,4-dioxane (4 mL) and DMSO (4 mL) isadded Cu(OAc)₂ (114 mg, 0.625 mmol). The mixture is heated at 60° C. for16 h then cooled to ambient temperature. EtOAc (12 ml) and brine (6 ml)is added followed by concentrated NH₄OH (0.6 mL) and the mixture isstirred at ambient temperature for 15 min. The layers are separated andthe aqueous layer is extracted with EtOAc (6 mL). The combined extractsare dried (Na₂SO₄) and evaporated. The residue is purified bypreparative TLC with 2:1 EtOAc/hexanes to give 104 mg (57%) white solid.

¹HNMR (400 MHz, CDCl₃): δ 8.17 (s, broad, 1H), 7.80-7.85 (m, 3H), 7.75(s, 1H), 7.69 (d, 2H), 7.54 (t, 1H), 7.39 (d, 1H), 2.16 (s, 3H).

LC_MS: M+1 360.11.

B. 4-((3-(trifluoromethoxy)phenyl)sulfonyl)aniline

To a solution ofN-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)acetamide (104 mg,0.29 mmol) in EtOH (8 mL) is added NaOH (10 M in water, 0.6 mL, 6 mmol).The mixture is heated at 80° C. for 4 h and the solvent is evaporated.The residue is partitioned between EtOAc (15 mL) and brine (10 mL) andthe layers are separated. The aqueous layer is extracted with EtOAc (10mL) and the combined extracts are dried (Na₂SO₄) and evaporated. Thewhite solid obtained (86 mg, 93%) is used to the next step withoutfurther purification.

¹HNMR (400 MHz, CDCl₃): δ 7.79 (d, 1H), 7.73 (s, 1H), 7.67 (d, 2H), 7.50(t, 1H), 7.34 (d, 1H), 6.66 (d, 2H), 4.28 (s, broad, 2H).

LC_MS: M+1 318.09.

C.3-(pyridin-3-yl)-N-(4-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)acrylamide

To a solution of 4-((3-(trifluoromethoxy)phenyl)sulfonyl)aniline (86,0.27 mmol) in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (58mg, 0.28 mmol) and K₂CO₃ (138 mg, 1 mmol). The mixture is heated at 50°C. for 2 h and the solvent is evaporated. The residue is partitionedbetween EtOAc (15 mL) and brine (10 mL) and the layers are separated.The aqueous layer is extracted with EtOAc (10 mL) and the combinedextracts are dried (Na₂SO₄) and evaporated. Purification of the residueby preparative TLC with 100:5:0.5 CH₂Cl₂/MeOH/NH₄OH gives the titledcompounds as a white solid (60 mg, 50%). (LC_MS: M+1 449.14; ¹HNMR (400MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.82 (d, 1H), 8.57 (dd, 1H), 7.89-8.06(m, 7H), 7.76 (t, 1H), 7.74 (m, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 6.91(d, 1H).

Example 5(E)-3-(pyridin-3-yl)-N-(4-(N-(2-(trifluoromethoxy)phenyl)sulfamoyl)phenyl)acrylamide

A: 4-nitro-N-(2-(trifluoromethoxy)phenyl)benzenesulfonamide

To a pre-cooled solution of 2-(trifluoromethoxy)aniline (1.8 g, 10.16mmol) in pyridine (20 ml) was added 4-nitrobenzene-1-sulfonyl chloride(2.252 g, 10.16 mmol) in 5-10 mL of pyridine at 0° C. slowly. Thereaction mixture was stirred and heated to 85° C. for 3 h, then cooleddown to 45° C. and stirred at the same temperature over weekend. Thesolvent was removed under reduced pressure. The residue was diluted withmethylene chloride and washed with 1N HCl (×2), water (×2), and brine.The organic layer was separated, dried with anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to give 2.82 g of title product.

¹H NMR (300 MHz, CDCl₃): δ 8.30-8.27 (dd, 2H), 7.96-7.93 (dd, 2H),7.74-7.71 (m, 2H), 7.34-7.26 (m, 2H), 7.22-7.16 (m, 1H), 6.92 (s, 1H).

LC-MS: 363 (M+H).

B: 4-amino-N-(2-(trifluoromethoxy)phenyl)benzenesulfonamide

To a mixture of 4-nitro-N-(2-(trifluoromethoxy)phenyl)benzenesulfonamide(2.62 g, 7.23 mmol) in EtOH (60 mL) was added Tin (II) chloridedehydrate (8.16 g, 36.2 mmol). The reaction mixture was stirred for 4 hat 80° C. LC-MS and TLC analyses indicated that the reaction wascompleted. The mixture was cooled down to room temperature. The EtOH wasremoved via vacuo and the residual was taken up in EtOAc (100 mL),followed by the addition of 2N NaOH (40 mL to make basic). Afterstirring vigorously for 1 h, the precipitates were filtered throughcelite and washed with EtOAc. The filtrate layers were separated. Theorganic layer was washed with 1N NaOH (optional), then water and brine,dried (Na₂SO₄), filtered, and concentrated. The crude product (brownresidue, 1.42 g) was subjected a column purification on BioTage (0-6%MeOH in DCM) to yield a desired product (1.23 g, 51% yield).

¹H NMR (300 MHz, CDCl₃): δ 7.68, 7.65 (dd, 1H), 7.56, 7.54 (dd, 2H),7.24-7.03 (m, 3H), 6.78 (s, 1H), 6.60-6.57 (m, 2H), 4.11 (s, 2H).

LC-MS: 333.04 (M+H).

C:(E)-3-(pyridin-3-yl)-N-(4-(N-(2-(trifluoromethoxy)phenyl)sulfamoyl)phenyl)acrylamide

To a mixture of 1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (66.0 mg,0.404 mmol), HATU (169 mg, 0.445 mmol) and Hunig's base (0.141 mL, 0.809mmol) in DMF (1.5 mL) was added (4-(phenylsulfonyl)phenyl)methanamine(100 mg, 0.404 mmol) to give a homogeneous solution. This solution wasstirred at room temperature overnight. The reaction mixture was dilutedwith EtOAc and washed successively with saturated aqueous NaHCO₃ andbrine. The organics were dried (Na₂SO₄), and concentrated. The residuewas dissolved in DCM and purified on BioTage to afford the desiredproduct (2.7 mg, 10% yield)

¹H NMR (300 MHz, CDCl₃): δ 8.53 (d, 1H), 8.50 (d, 1H), 7.91 (d, 2H),7.68 (d, 1H), 7.61-7.39 (m, 5H), 7.24-7.20 (m, 2H), 6.69 (d, 2H), 6.14(d, 1H).

LCMS: 464.15 (M+H).

Example 6(E)-N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)benzyl)-3-(pyridin-3-yl)acrylamide

In a 25 mL round-bottomed flask was added (E)-3-(pyridin-3-yl)acrylicacid (38.0 mg, 0.255 mmol),N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (48.9 mg,0.255 mmol) and 1-Hydroxybenzotriazole hydrate (39.0 mg, 0.255 mmol) inTetrahydrofuran (Volume: 4 ml) to give a light yellow suspension.Diisopropylethylamine (0.089 ml, 0.510 mmol) and(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)phenyl)methanamine (48mg, 0.170 mmol; prepared according to example 5) were added sequentiallyand the suspension was allowed to stir at room temperature overnightbefore being filtered through Celite®. The cake was washed with THF thenthe combined filtrate was concentrated in vacuo and the resultingresidue was purified by Preparative-HPLC to afford the product (68.0mg).

¹H NMR: (CDCl3, 500 MHz) δ_(H) 9.05 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H),8.15 (s, 1H), 7.88 (d, 1H), 7.61 (d, 2H), 7.44 (d, 2H), 7.11 (s, 1H),6.68 (d, 1H), 4.63 (d, 2H), 4.34 (s, 1H), 3.33 (d, 2H), 2.57 (d, 2H) and1.96 (m, 4H).

LCMS: 414.0 (MH⁺)

Assays Assay Example 1 Biochemical Inhibition Assay

NAMPT protein purification

Recombinant His-tagged NAMPT was produced in E. coli cells, purifiedover a Ni column, and further purified over a size-exclusion column byXTAL Biostructures.

The NAMPT Enzymatic Reaction

The NAMPT enzymatic reactions were carried out in Buffer A (50 mM HepespH 7.5, 50 mM NaCl, 5 mM MgCl₂, and 1 mM THP) in 96-well V-bottomplates. The compound titrations were performed in a separate dilutionplate by serially diluting the compounds in DMSO to make a 100× stock.Buffer A (89 μL) containing 33 nM of NAMPT protein was added to 1 μL of100× compound plate containing controls (e.g. DMSO or blank). Thecompound and enzyme mix was incubated for 15 minutes at roomtemperature, then 10 μL of 10× substrate and co-factors in Buffer A wereadded to the test well to make a final concentration of 1 μM NAM, 100 μM5-Phospho-D-ribose 1-diphosphate (PRPP), and 2.5 mM Adenosine5′-triphosphate (ATP). The reaction was allowed to proceed for 30minutes at room temperature, then was quenched with the addition of 11μL of a solution of formic acid and L-Cystathionine to make a finalconcentration of 1% formic acid and 10 μM L-Cystathionine. Backgroundand signal strength was determined by addition (or non-addition) of aserial dilution of NMN to a pre-quenched enzyme and cofactor mix.

Quantification of NMN

A mass spectrometry-based assay was used to measure the NAMPT reactionproduct (NMN) and the internal control (L-Cystathionine). NMN andL-Cystathionine were detected using the services of Biocius Lifescienceswith the RapidFire system. In short, the NMN and L-Cystathionine arebound to a graphitic carbon cartridge in 0.1% formic acid, eluted in 30%acetonitrile buffer, and injected into a Sciex 4000 mass spectrometer.The components of the sample were ionized with electrospray ionizationand the positive ions were detected. The Q1 (parent ion) and Q3(fragment ion) masses of NMN were 334.2 and 123.2, respectively. The Q1and Q3 for L-Cystathionine were 223.1 and 134.1, respectively. Thefragments are quantified and the analyzed by the following method.

% Inhibitions are Determined Using this Method.

First the NMN signal is normalized to the L-Cystathionine signal bydividing the NMN signal by the L-Cystathionine signal for each well. Thesignal from the background wells are averaged and subtracted from thetest plates. The compound treated cells re then assayed for % inhibitionby using this formula.% Inh=100−100*x/y

Wherein x denotes the average signal of the compound treated wells and ydenotes the average signal of the DMSO treated wells.

IC50s are Determined Using Excel and this Formula.IC50=10^(LOG 10(X)+(((50−% Inh at Cmpd Concentration 1)/(XX−YY)*(LOG10(X)−LOG 10(Y))))

Wherein X denotes the compound concentration 1, Y denotes the compoundconcentration 2, XX denotes the % inhibition at compound concentration 1(X), and YY denotes the % inhibition at compound concentration 2 (Y).

The NAMPT-inhibitor compounds of this invention have IC50 values thatare under 10 μM, preferably under 1 μM, more preferably under 0.1 μM andmost preferably under 0.01 μM. Results for the compounds are provided inTable 3 below.

Assay Example 2 In-Vitro Cell Proliferation Assay

A2780 cells were seeded in 96-well plates at 1×10³ cells/well in 180 μLof culture medium (10% FBS, 1% Pen/Strep Amphotecricin B, RPMI-1640)with and without the addition of either β-nicotinamide mononucleotide(NMN) or nicotinamide (NAM). After overnight incubation at 37° C. and 5%CO₂, the compound titrations were performed in a separate dilution plateby serially diluting the compounds in DMSO to make a 1000× stock. Thecompounds were then further diluted to 10× final concentration inculture media, whereupon 20 μL of each dilution was added to the platedcells with controls (e.g. DMSO and blank) to make a final volume of 200μL. The final DMSO concentration in each well was 0.1%. The plates werethen incubated for 72 hours at 37° C. in a 5% CO₂ incubator. The numberof viable cells was then assessed using sulforhodamine B (SRB) assay.Cells were fixed at 4° C. for 1 hour with the addition of 50 μL 30%trichloroacetic acid (TCA) to make a final concentration of 6% TCA. Theplates were washed four times with H₂O and allowed to dry for at least 1hour, whereupon 100 μL of a 4% SRB in 1% acetic acid solution was addedto each well and incubated at room temperature for at least 30 minutes.The plates were then washed three times with 1% acetic acid, dried, andtreated with 100 μL of 10 mM Tris-Base solution. The plates were thenread in a microplate reader at an absorbance of 570 nm. Background wasgenerated on a separate plate with media only.

Method for Determining % Inhibition

First, the signals from the background plate are averaged and then thebackground was subtracted from the test plates. The compound-treatedcells were then assayed for % inhibition by using the following formula:% Inh=100−100*x/y

wherein x denotes the average signal of the compound-treated cells and ydenotes the average signal of the DMSO-treated cells.

Formula for Determining IC₅₀ Values:IC50=10^(LOG 10(X)+(((50−% Inh at Cmpd Concentration 1)/(XX−YY)*(LOG10(X)−LOG 10(Y))))

wherein X denotes the compound concentration 1, Y denotes the compoundconcentration 2, XX denotes the % inhibition at compound concentration 1(X), and YY denotes the % inhibition at compound concentration 2 (Y).

Specificity of Cytotoxicity

Inhibition of NAMPT could be reversed by the addition of NAM or NMN. Thespecificity of the compounds were determined via cell viability assay inthe presence of the compound and either NAM or NMN. Percent inhibitionswere determined using the method given above.

The NAMPT-inhibitor compounds of this invention have IC50 values thatare under 10 μM, preferably under 1 μM, more preferably under 0.1 μM andmost preferably under 0.01 μM. Results for the compounds is provided inTable 3 below.

TABLE 3 Biochem A2780 IC50 IC50 IUPAC Name uM uM(2E)-3-(pyridin-3-yl)-N-(4-{[2- 0.0036 0.0157(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2- enamide(2E)-3-(pyridin-3-yl)-N-(4-{[2- 0.375 1.27(trifluoromethoxy)phenyl]sulfamoyl}phenyl)prop-2- enamide(2E)-3-(pyridin-3-yl)-N-(4-{[3- 0.0615 0.0477(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2- enamide(2E)-3-(pyridin-3-yl)-N-(4-{[3- 0.0319 0.107(trifluoromethyl)benzene]sulfonyl}phenyl)prop-2-enamide(2E)-3-(pyridin-3-yl)-N-(4-{[4- 0.167 0.1-1(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2- enamide(2E)-3-(pyridin-3-yl)-N-(4-{[4- 0.0565 0.1-1(trifluoromethyl)benzene]sulfonyl}phenyl)prop-2-enamide(2E)-3-(pyridin-3-yl)-N-[4-(pyridine-3- 0.0183 0.1-1sulfonyl)phenyl]prop-2-enamide (2E)-3-(pyridin-3-yl)-N-[4-(quinoline-3-0.0037 0.1 sulfonyl)phenyl]prop-2-enamide(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-6- 0.0054 0.0762sulfonyl)phenyl]prop-2-enamide (2E)-3-(pyridin-3-yl)-N-[4-(quinoline-8-0.0036 0.0122 sulfonyl)phenyl]prop-2-enamide(2E)-3-(pyridin-3-yl)-N-{4-[(3- 0.0099 0.1-1sulfamoylbenzene)sulfonyl]phenyl}prop-2-enamide(2E)-3-(pyridin-3-yl)-N-{4-[5-(pyrrolidin-1-yl)pyridine-3- 0.0014 0.0511sulfonyl]phenyl}prop-2-enamide (2E)-N-(4-{[2-chloro-5- 0.021 0.1-1(trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[2-methoxy-4- 0.0596 0.118(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[2-methoxy-5-(propan-2- 0.0026 0.0167yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2- enamide(2E)-N-(4-{[2-methoxy-5- 0.0168 0.0293(trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[2-methoxy-5- 0.0242 0.019(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[2-methyl-4- 0.0628 0.1-1(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[3-(1H-pyrazol-1- 0.0048 0.088yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2- enamide(2E)-N-(4-{[3-(2- 0.0567 0.1-1methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3- yl)prop-2-enamide(2E)-N-(4-{[3-(3,5-dimethyl-1H-pyrazol-1- 0.0091 0.0319yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2- enamide(2E)-N-(4-{[3-(ethanesulfonyl)benzene]sulfonyl}phenyl)- 0.0173 0.07043-(pyridin-3-yl)prop-2-enamide(2E)-N-(4-{[3-(methoxymethyl)benzene]sulfonyl}phenyl)- 0.0077 0.0783-(pyridin-3-yl)prop-2-enamide(2E)-N-(4-{[3-(morpholin-4-yl)benzene]sulfonyl}phenyl)- 0.0092 0.03033-(pyridin-3-yl)prop-2-enamide(2E)-N-(4-{[3-(propan-2-yloxy)benzene]sulfonyl}phenyl)- 0.0011 0.04893-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[3-chloro-4- 0.0434 0.1-1(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[3-chloro-5- 0.0081 0.0583(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[3-fluoro-5-(2- 0.0354 0.0613methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3- yl)prop-2-enamide(2E)-N-(4-{[4-(1H-pyrazol-1- 0.0174 0.0717yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2- enamide(2E)-N-(4-{[4-(ethoxymethyl)benzene]sulfonyl}phenyl)- 0.0078 0.1-13-(pyridin-3-yl)prop-2-enamide(2E)-N-(4-{[4-(morpholin-4-yl)benzene]sulfonyl}phenyl)- 0.0248 0.05533-(pyridin-3-yl)prop-2-enamide(2E)-N-(4-{[4-(propan-2-yloxy)benzene]sulfonyl}phenyl)- 0.0054 0.09153-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{[4-chloro-3- 0.0184 0.122(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-(4-{8-oxatricyclo[7.4.0.0²,⁷]trideca- 0.00350.0073 1(13),2,4,6,9,11-hexaene-6-sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide (2E)-N-[(4-{8-oxa-3-azabicyclo[3.2.1]octane-3- 0.0030.386 sulfonyl}phenyl)methyl]-3-(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-benzothiophene-7-sulfonyl)phenyl]-3- 0.0161 0.106(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1H-indole-4-sulfonyl)phenyl]-3-(pyridin-3- 0.0023 0.0401yl)prop-2-enamide (2E)-N-[4-(1H-indole-7-sulfonyl)phenyl]-3-(pyridin-3-0.0084 0.0133 yl)prop-2-enamide(2E)-N-[4-(1-methyl-1H-indazole-5-sulfonyl)phenyl]-3- 0.0019 0.0976(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-methyl-1H-indazole-6-sulfonyl)phenyl]-3- 0.0026 0.053(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-methyl-1H-indazole-7-sulfonyl)phenyl]-3- 0.0089 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-methyl-1H-indole-2-sulfonyl)phenyl]-3- 0.0218 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]-3- 0.0077 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(1-propyl-1H-pyrazole-4-sulfonyl)phenyl]-3- 0.0026 0.0208(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(2,3-dihydro-1-benzofuran-7-sulfonyl)phenyl]- 0.0049 0.03613-(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(2H-1,3-benzodioxole-4-sulfonyl)phenyl]-3- 0.0161 0.0751(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]-3- 0.0099 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(2-methylpyridine-3-sulfonyl)phenyl]-3- 0.009 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(4-methylpyridine-3-sulfonyl)phenyl]-3- 0.0204 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(5-methoxypyridine-3-sulfonyl)phenyl]-3- 0.0156 0.0863(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(5-methylpyridine-3-sulfonyl)phenyl]-3- 0.0181 0.0744(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(5-methylthiophene-2-sulfonyl)phenyl]-3- 0.0166 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(6-methoxynaphthalene-2-sulfonyl)phenyl]-3- 0.0059 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(6-methylpyridine-3-sulfonyl)phenyl]-3- 0.0374 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-[4-(benzenesulfonyl)phenyl]-3-(pyridin-3-yl)prop- 0.004 0.0812-enamide (2E)-N-[4-(isoquinoline-4-sulfonyl)phenyl]-3-(pyridin-3-0.00245 0.0217 yl)prop-2-enamide(2E)-N-[4-(naphthalene-1-sulfonyl)phenyl]-3-(pyridin-3- 0.0042 0.0181yl)prop-2-enamide(2E)-N-[4-(phenoxathiine-4-sulfonyl)phenyl]-3-(pyridin- 0.0072 0.05013-yl)prop-2-enamide(2E)-N-{[4-(benzenesulfonyl)phenyl]methyl}-3-(pyridin- 0.003 0.2433-yl)prop-2-enamide (2E)-N-{4-[(2,5-dichlorobenzene)sulfonyl]phenyl}-3-0.0224 0.1-1 (pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(2-methoxy-5-0.0018 0.0073 methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(2-methoxybenzene)sulfonyl]phenyl}-3- 0.0077 0.0241(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(2-methylbenzene)sulfonyl]phenyl}-3- 0.0333 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,4-dichlorobenzene)sulfonyl]phenyl}-3- 0.0729 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,4-dimethoxybenzene)sulfonyl]phenyl}-3- 0.0025 0.0436(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,5-dichlorobenzene)sulfonyl]phenyl}-3- 0.0505 0.186(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,5-dimethoxybenzene)sulfonyl]phenyl}-3- 0.0203 0.0443(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,5-dimethylbenzene)sulfonyl]phenyl}-3- 0.0171 0.0954(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(3-chloro-4- 0.0058 0.123methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(3-chloro-4-methylbenzene)sulfonyl]phenyl}- 0.0086 0.1993-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(3-chloro-4- 0.0056 0.1-1propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(3-chloro-5-fluorobenzene)sulfonyl]phenyl}- 0.124 0.1793-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(3-chloro-5- 0.022 0.1methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(3-chloro-5-methylbenzene)sulfonyl]phenyl}- 0.0062 0.08183-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-chlorobenzene)sulfonyl]phenyl}-3-(pyridin- 0.122 0.1823-yl)prop-2-enamide (2E)-N-{4-[(3- 0.0081 0.1-1ethanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(3-ethoxybenzene)sulfonyl]phenyl}-3- 0.05720.0919 (pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-ethylbenzene)sulfonyl]phenyl}-3-(pyridin- 0.0033 0.03053-yl)prop-2-enamide (2E)-N-{4-[(3-fluoro-4- 0.0115 0.103methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(3-fluoro-4-methylbenzene)sulfonyl]phenyl}- 0.0276 0.1963-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-fluoro-4-propoxybenzene)sulfonyl]phenyl}- 0.0409 0.1-13-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(3-fluoro-5- 0.0032 0.0681methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(3-fluoro-5-methylbenzene)sulfonyl]phenyl}- 0.0175 0.1083-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-fluorobenzene)sulfonyl]phenyl}-3-(pyridin- 0.0664 0.1033-yl)prop-2-enamide (2E)-N-{4-[(3- 0.0075 0.1-1methanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-methanesulfonylbenzene)sulfonyl]phenyl}- 0.0143 0.1-13-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-methoxybenzene)sulfonyl]phenyl}-3- 0.0857 0.114(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-methylbenzene)sulfonyl]phenyl}-3- 0.0323 0.0933(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-phenylbenzene)sulfonyl]phenyl}-3- 0.0254 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3-propoxybenzene)sulfonyl]phenyl}-3- 0.0216 0.0868(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(4-chloro-2-ethoxybenzene)sulfonyl]phenyl}- 0.0042 0.009683-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(4-chloro-2- 0.0073 0.109methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(4-chloro-3- 0.0263 0.072methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(4-chlorobenzene)sulfonyl]phenyl}-3-(pyridin- 0.0435 0.1-13-yl)prop-2-enamide(2E)-N-{4-[(4-ethoxy-3-fluorobenzene)sulfonyl]phenyl}- 0.0341 0.1753-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(4-ethoxybenzene)sulfonyl]phenyl}-3- 0.0274 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(4-fluoro-3-methylbenzene)sulfonyl]phenyl}- 0.0219 0.1-13-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(4-fluorobenzene)sulfonyl]phenyl}-3-(pyridin- 0.002 0.1583-yl)prop-2-enamide(2E)-N-{4-[(4-methanesulfonylbenzene)sulfonyl]phenyl}- 0.0114 0.1-13-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(4-methoxy-3,5- 0.0067 0.0495dimethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(4-methoxy-3- 0.0171 0.116methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(4-phenylbenzene)sulfonyl]phenyl}-3- 0.0045 0.1-1(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(5-chloro-2-ethoxybenzene)sulfonyl]phenyl}- 0.0123 0.005593-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[(5-chloro-2- 0.0046 0.0126methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(5-fluoro-2- 0.0145 0.0205methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2- enamide(2E)-N-{4-[(5-fluoro-2-methylbenzene)sulfonyl]phenyl}- 0.0074 0.09013-(pyridin-3-yl)prop-2-enamide (2E)-N-{4-[2-(dimethylamino)pyrimidine-5-0.0079 0.0731 sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[2-(morpholin-4-yl)pyridine-3- 0.0806 0.1-1sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2E)-N-{4[4-(morpholin-4-yl)piperidine-1- 0.01 0.21sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[6-(dimethylamino)pyridine-3- 0.0051 0.0781sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2Z)-N-[4-(benzenesulfonyl)phenyl]-2-fluoro-3-(pyridin- 0.007 0.3473-yl)prop-2-enamide3-chloro-N,N-diethyl-5-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0194 0.0274enamido]benzene}sulfonyl)benzamideN-(2-methylpropyl)-3-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0213 0.1-1enamido]benzene}sulfonyl)benzamideN-(propan-2-yl)-3-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0176 0.1-1enamido]benzene}sulfonyl)benzamideN-cyclopentyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0161 0.1-1enamido]benzene}sulfonyl)benzamideN-cyclopropyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0059 0.1-1enamido]benzene}sulfonyl)benzamideN-ethyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0073 0.1-1enamido]benzene}sulfonyl)benzamideN-ethyl-4-({4-[(2E)-3-(pyridin-3-yl)prop-2- 0.0147 0.1-1enamido]benzene}sulfonyl)benzamide

We claim:
 1. A compound of Formula IB:

wherein: Ar is aryl or heteroaryl, each of said aryl and heteroarylbeing either unsubstituted or optionally independently substituted with1, 2, 3, or 4 substituents which can be the same or different and areindependently selected from the group consisting of: deuterium, halo,cyano, amino, aminoalkyl-, (amino)alkoxy-, —CONH₂, —C(O)NH(alkyl),—C(O)N(alkyl)₂, —C(O)NH(aryl), —C(O)N(aryl)₂, —CH_(z)F_(3-z),—OCH_(z)F_(3-z), -alkyl, -alkenyl, -alkynyl, -alkoxy,(alkoxyalkyl)amino-, —N(R³)—C(O)-alkyl, —N(R³)—C(O)-aryl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl; R¹ is —NR^(a)R^(b), wherein R^(a)is H, alkyl, or —S(O)₂alkyl and R^(b) is alkyl, hydroxyalkyl,—S(O)₂alkyl, —(CH₂)_(q)cycloalkyl, —(CH₂)_(q)heterocycloalkyl, aryl,arylalkyl-, —(CH₂)_(q)heteroaryl; cycloalkyl; heterocycloalkyl; aryl;heteroaryl; each of said cycloalkyl, heterocycloalkyl, aryl, orheteroaryl is unsubstituted or substituted with 1, 2, 3, 4, or 5substituents which can be the same or different and are independentlyselected from the group consisting of: deuterium, halo, cyano, alkyl,hydroxyl, hydroxyalkyl, hydroxyalkoxy, cyanoalkyl, haloalkyl, alkenyl,alkynyl, alkoxy, alkylalkoxy, haloalkoxy, arylalkenyl-, aryloxy,benzyloxy, oxo, —(CH₂)_(q)—NR^(c)R^(d), —(CH₂)_(q)—CONR^(c)R^(d),—S(O)₂-alkyl, —S(O)₂-aryl, S(O)₂NH₂, —S(O)₂NH-alkyl, —S(O)₂N(alkyl)₂,—S(O)₂-heterocycloalkyl, —S(O)₂—CF₃, —C(O)alkyl, —C(O)aryl,—C(O)alkylenylaryl, —C(O)O-alkyl, —NH—C(O)alkyl, —NH—C(O)aryl,methylenedioxy, —(CH₂)_(q)cycloalkyl, cycloalkylalkoxy-, aryl,arylalkyl-, —(CH₂)_(q)heteroaryl, and —(CH₂)_(q)heterocycloalkyl,wherein each of said cycloalkyl, heterocycloalkyl, aryl or heteroarylmay be substituted by one or more halo, nitro, haloalkyl, haloalkoxy,oxo, cyano, alkyl, haloalkyl, or alkoxy and; R^(c) and R^(d) areindependently selected from the group consisting of H, alkyl,hydroxyalkyl, alkoxy, aryl, alkoxyalkyl, —S(O)₂alkyl and cycloalkyl orR^(C) and R^(d) can form a 5 or 6 membered heterocycloalkyl grouptogether with the nitrogen atom to which they are attached, wherein saidheterocycloalkyl group may contain one or more addional heteroatom(s)selected from N, S or O; z is 0, 1 or 2; q is 0, 1, 2, 3 or 4; or apharmaceutically acceptable salt thereof, with the proviso that thecompound of formula IB is not:N-[3-(cyclopentylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[4-ethoxy-3-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[2-(1-methylethoxy)-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[2-ethoxy-5-(4-morpholinylsulfonyl)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[5-[(hexahydro-1Hazepin-1-yl)sulfonyl]-2-(2,2,2-trifluoroethoxy)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[5-[(diethylamino)sulfonyl]-2-(4-morpholinyl)phenyl]-3-(3-pyridinyl)-2-propenamide;N-[3-[[(3-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;N-[3-[[(4-chlorophenyl)amino]sulfonyl]-4-methylphenyl]-3-(3-pyridinyl)-2-propenamide;3-(3-pyridinyl)-N-[4-[[(tetrahydro-1,1-dioxido-3-thienyl)amino]sulfonyl]phenyl]-2-propenamide;3-(3-pyridinyl)-N-[3-[[[3-(trifluoromethyl)phenyl]amino]sulfonyl]phenyl]-2-propenamide;or3-(3-pyridinyl)-N-[1,4,5,6-tetrahydro-5-[(4-methylphenyl)sulfonyl]pyrrolo[3,4-c]pyrazol-3-yl]-2-propenamide.2. The compound of claim 1, wherein Ar is aryl.
 3. The compound of claim1, wherein Ar is phenyl.
 4. The compound of claim 1, wherein Ar is:


5. The compound of claim 1, wherein R¹ is —NR^(a)R^(b).
 6. The compoundof claim 5 , wherein R^(a) is H, C₁-C₆-alkyL or —S(O)₂—C₁-C₆-alkyl, andR^(b) is C_(1-C) ₆-alkyl, hydroxyl-C₁-C₆-alkyl, —S(O)₂-C_(1-C) ₆-alkyl,—(CH₂)_(q)—C₃-C6-cycloalkyl, —(CH₂)_(q)heterocycloalkyl, phenyl,phenylalkyl-, or —(CH₂)_(q)heteroaryl, wherein heterocycloalkyl groupsare 5 or 6 membered heterocycloalkyl groups containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S andwherein heteroaryl groups are 5 or 6 membered heteroaryl groupscontaining 1, 2, or 3 heteroatoms selected from the group consisting ofN, O, and S.
 7. The compound of claim 1, wherein R¹ is cycloalkyl. 8.The compound of claim 1, wherein R¹ is aryl.
 9. The compound of claim 1,wherein R¹ is heterocycloalkyl.
 10. The compound of claim 1, wherein R¹is heteroaryl.
 11. The compound of claim 1, wherein R¹ is a 5 to 14membered monocyclic or bicyclic heteroaryl group containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S.
 12. Thecompound of claim 1, wherein R¹ is selected from the group consistingof: pyridine, pyrazole, thiophene, pyrimidine, 1H-indole, quinoline,isoquinoline, 1H-indazole, benzothiophene, phenoxathiine,2H-1,3-benzodioxole, 2,3-dihydro-l-benzofuran, and8-oxatricyclo[7.4.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene.
 13. Thecompound of claim 1, wherein R¹ is selected from the group consistingof: (1H-pyrazol-1-yl)benzene; 1-benzothiophene; 1H-indole;1-methyl-1H-indazole; 1-methyl-1H -indole; 1-methyl-1H-pyrazole;2-(dimethylamino)pyrimidine; 2-(morpholin-4-yl)pyridine;2-(trifluoromethoxy)benzene; 2,3-dihydro-1-benzofuran;2,5-dichlorobenzene; 2-chloro-5-(trifluoromethoxy)benzene;2H-1,3-benzodioxole; 2-methoxy-4-(trifluoromethyl)benzene;2-methoxy-5-(propan-2-yl)benzene; 2-methoxy-5-(trifluoromethoxy)benzene;2-methoxy-5-(trifluoromethyl)benzene; 2-methoxy-5-methylbenzene;2-methoxybenzene; 2-methyl-4-(trifluoromethyl)benzene; 2-methylbenzene;3-(2-methylpropoxy)benzene; 3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene;3-(ethanesulfonyl)benzene; 3-(methoxymethyl)benzene;3-(morpholin-4-yl)benzene; 3-(propan-2-yloxy)benzene;3-(trifluoromethoxy)benzene; 3-(trifluoromethyl)benzene;3,4-dichlorobenzene; 3,4-dimethoxybenzene; 3,5-dichlorobenzene;3,5-dimethoxybenzene; 3,5-dimethylbenzene;3-chloro-4-(trifluoromethyl)benzene; 3-chloro-4-methoxybenzene;3-chloro-4-methylbenzene; 3-chloro-4-propoxybenzene;3-chloro-5-(trifluoromethyl)benzene; 3-chloro-5-fluorobenzene;3-chloro-5-methoxybenzene; 3-chloro-5-methylbenzene; 3-chlorobenzene;3-ethanesulfonamidobenzene; 3-ethoxybenzene; 3-ethylbenzene;3-fluoro-4-methoxybenzene; 3-fluoro-4-methylbenzene;3-fluoro-4-propoxybenzene; 3-fluoro-5-(2-methylpropoxy)benzene;3-fluoro-5-methoxybenzene); 3-fluoro-5-methylbenzene; 3-fluorobenzene;3-methanesulfonamidobenzene; 3-methanesulfonylbenzene; 3-methoxybenzene;3-methylbenzene; 3-phenylbenzene; 3-propoxybenzene;4-(1-methyl-1H-indazole; 4-(2-methylpyridine; 4-(ethoxymethyl)benzene;4-(morpholin-4-yl)benzene; 4-(propan-2-yloxy)benzene;4-(trifluoromethoxy)benzene; 4-(trifluoromethyl)benzene;4-chloro-2-ethoxybenzene; 4-chloro-2-methoxybenzene;4-chloro-3-(trifluoromethyl)benzene; 4-chloro-3-methoxybenzene;4-chlorobenzene; 4-ethoxy-3-fluorobenzene; 4-ethoxybenzene;4-fluoro-3-methylbenzene; 4-fluorobenzene; 4-methanesulfonylbenzene;4-methoxy-3,5-dimethylbenzene; 4-methoxy-3-methylbenzene;4-methylpyridine; 4-phenylbenzene; 5-(pyrrolidin-l-yl)pyridine;5-chloro-2-ethoxybenzene; 5-chloro-2-methoxybenzene;5-fluoro-2-methoxybenzene; 5-fluoro-2-methylbenzene; 5-methoxypyridine;5-methylpyridine; 5-methylthiophene; 6-(dimethylamino)pyridine;6-methoxynaphthalene; 6-methylpyridine; 8-oxa-3-azabicyclo[3.2.1]octane;8-oxatricyclo[7.4.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene; isoquinoline;morpholin-4-yl; naphthalene; phenoxathiine; phenyl; pyridin-3-yl;pyridine; and quinoline.
 14. A compound selected from the groupconsisting of:(2E)-N-(4-{[3-fluoro-5-(2-methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluoro-4-propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide; 4-(phenoxathiine-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(2,5-dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;N-ethyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;4-(2H-1,3-benzodioxole-5-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;4-(2,3-dihydro-1-benzofuran-7-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-fluoro-3-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(2-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide 4-(2-methylpyridine-3-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[4-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;4-(naphthalene-1-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluoro-4-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-chlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;N-ethyl-4-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;(2E)-N-{4-[(3-chloro-4-propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide; (2E)-N-(4-{[3-(1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(5-chloro-2-ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(1-methyl-1H-indazole-6-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-chloro-4-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide; (2E)-3-(pyridin-3-yl)-N-(4-{[4-(trifluoromethyl)benzene]sulfonyl}phenyl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-(4-{[3-(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2-enamide;(2E)-N-(4-{[2-methoxy-5-(propan-2-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;4-(1H-indole-7- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-{4-[5-(pyrrolidin-1-yl)pyridine-3-sulfonyl]phenyl}prop-2-enamide;(2E)-N-(4-{[3-chloro-5-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;4-(1-methyl-1H-indole-2-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-(4-{[4-(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2-enamide;(2E)-N-{4-[(3-chloro-4-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(6-methoxynaphthalene-2-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-ethoxy-3-fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluoro-5-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3,4-dimethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[4-(morpholin-4-yl)piperidine-1-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-3-sulfonyl)phenyl]prop-2-enamide;(2E)-N-(4-{[2-chloro-5-(trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-phenylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluorobenzene)sulfonyl]phenyl }-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-methylbenzene)sulfonyl]phenyl }-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3,5-dimethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(5-methoxypyridine-3- sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-chlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-chloro-5-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-methanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(5-methylpyridine-3-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-(methoxymethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(4-{8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl}phenyl)methyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3,5-dimethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(5-fluoro-2-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-(4-{[2-(trifluoromethoxy)phenyl]sulfamoyl}phenyl)prop-2-enamide;4-(6-methylpyridine-3-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;4-(isoquinoline-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;3-chloro-N,N-diethyl-5-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;(2E)-N-{4-[(4-methoxy-3-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(benzenesulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;N-cyclopentyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;(2E)-N-{4-[(3-methanesulfonylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[2-(morpholin-4-yl)pyridine-3-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-(4-{[2-(trifluoromethoxy)benzene]sulfonyl}phenyl)prop-2-enamide;N-(propan-2-yl)-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide; (2E)-3-(pyridin-3-yl)-N-(4-{[3-(trifluoromethyl)benzene]sulfonyl}phenyl)prop-2-enamide;4-(1-benzothiophene-7-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[2-(dimethylamino)pyrimidine-5-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluoro-4-methylbenzene)sulfonyl]phenyl }-3-(pyridin-3-yl)prop-2-enamide;4-(1H-indole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{[4-(benzenesulfonyl)phenyl]methyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-8-sulfonyl)phenyl]prop-2-enamide;(2E)-N-(4-{[2-methoxy-5-(trifluoromethoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(5-methylthiophene-2-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-chloro-3-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[2-methoxy-4-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;N-(2-methylpropyl)-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;N-cyclopropyl-3-({4-[(2E)-3-(pyridin-3-yl)prop-2-enamido]benzene}sulfonyl)benzamide;(2Z)-N-[4-(benzenesulfonyl)phenyl]-2-fluoro-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-fluoro-5-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[2-methyl-4-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;4-(1-propyl-1H-pyrazole-4-sulfonyl)phenyl1-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[4-(ethoxymethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-methanesulfonylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-methoxy-3,5-dimethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(5-chloro-2-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[4-(morpholin-4-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-[4-(pyridine-3-sulfonyl)phenyl]prop-2-enamide;(2E)-N-(4-{[3-(propan-2-yloxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-chloro-2-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-(2-methylpropoxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-ethylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-[4-(quinoline-6-sulfonyl)phenyl]prop-2-enamide;(2E)-N-{4-[(3-chloro-5-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(2-methoxy-5-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide(2E)-N-{4-[(3,5-dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-(morpholin-4-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-(3,5-dimethyl-1H-pyrazol-1-yl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-propoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{8-oxatricyclo[7.4.0.0²,⁷]trideca-1(13),2,4,6,9,11-hexaene-6-sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(5-fluoro-2-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(1-methyl-1H-indazole-5-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[4-(propan-2-yloxy)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-chloro-4-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-3-(pyridin-3-yl)-N-{4-[(3-sulfamoylbenzene)sulfonyl]phenyl}prop-2-enamide;(2E)-N-{4-[(3-methoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(2-methylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(2H-1,3-benzodioxole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-ethanesulfonamidobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(4-methylpyridine-3-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;4-(1-methyl-1H-indazole-7-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3,4-dichlorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;4-(1-methyl-1H-pyrazole-4-sulfonyl)phenyl]-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[4-chloro-3-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[2-methoxy-5-(trifluoromethyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-(4-{[3-(ethanesulfonyl)benzene]sulfonyl}phenyl)-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-chloro-5-fluorobenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(4-chloro-2-ethoxybenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;(2E)-N-{4-[(3-phenylbenzene)sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;and(2E)-N-{4-[6-(dimethylamino)pyridine-3-sulfonyl]phenyl}-3-(pyridin-3-yl)prop-2-enamide;and pharmaceutically acceptable salts thereof.
 15. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 16.The pharmaceutical composition of claim 15, further comprising achemotherapeutic agent.
 17. The pharmaceutical composition of claim 16,wherein said chemotherapeutic agent is a DNA damaging agent.
 18. Thepharmaceutical composition of claim 15, further comprising a cellrescuing agent.
 19. The pharmaceutical composition of claim 18, whereinsaid cell rescuing agent is selected from the group consisting ofnicotinamide, nicotinic acid, and nicotinamide mononucleotide.
 20. Thepharmaceutical composition of claim 19, wherein said chemotherapeuticagent is selected from the group consisting of: cytotoxic agent,cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan,camptostar, topotecan, paclitaxel, docetaxel, the epothilones,tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, tipifarnib, R115777, L778,123, BMS 214662,gefitnib, erlotinib, C225, ibantinib mesylate, interferon alfa-2b,peginterferon alfa-2b, aromatase combinations, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,oxaliplatin, Pentostatine, Vinblastine, Vincristine, Vindesine,Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine,Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda,Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine,Melphalan, Trastuzumab, Fulvestrant, Exemestane, Ifosfomide, Rituximab,Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin,chlorambucil, letrozole, megestrol, and valrumbicin.
 21. A method totreat a condition caused by an elevated level of NAMPT in a patient byadministering a therapeutically effective amount of at least onecompounds of claim 1, or a pharmaceutically acceptable salt thereof,wherein said condition is a cancer.
 22. The method of claim 21, whereinsaid condition is ovarian cancer.